• Synaptic transmission;
  • Epilepsy;
  • Presynaptic;
  • Postsynaptic;
  • Neuropeptides;
  • Synaptic vesciles;
  • Antiepileptic drugs


  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Synaptic transmission is the communication between a presynaptic and a postsynaptic neuron, and the subsequent processing of the signal. These processes are complex and highly regulated, reflecting their importance in normal brain functioning and homeostasis. Sustaining synaptic transmission depends on the continuing cycle of synaptic vesicle formation, release, and endocytosis, which requires proteins such as dynamin, syndapin, synapsin, and synaptic vesicle protein 2A. Synaptic transmission is regulated by diverse mechanisms, including presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors and signaling, and modulators of neurotransmission. Neurotransmitters released presynaptically can bind to their postsynaptic receptors, the inhibitory γ-aminobutyric acid (GABA)ergic receptors or the excitatory glutamate receptors. Once released, glutamate activates a variety of postsynaptic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), kainate, and metabotropic receptors. The activation of the receptors triggers downstream signaling cascades generating a vast array of effects, which can be modulated by a numerous auxiliary regulatory subunits. Moreover, different neuropeptides such as neuropeptide Y, brain-derived neurotrophic factor (BDNF), somatostatin, ghrelin, and galanin, act as regulators of diverse synaptic functions and along with the classic neurotransmitters. Abnormalities in the regulation of synaptic transmission play a critical role in the pathogenesis of numerous brain diseases, including epilepsy. This review focuses on the different mechanisms involved in the regulation of synaptic transmission, which may play a role in the pathogenesis of epilepsy: the presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors, and modulators of neurotransmission, including the mechanism by which drugs can modulate the frequency and severity of epileptic seizures.

Synaptic transmission is the process by which neurotransmitters released from the presynaptic neuronal terminal bind to, and activate, receptors on the postsynaptic neuron, and the subsequent processing of the signal. When the neurons are communicating in a healthy brain, an appropriated integration of sensory input and a balance between excitatory and inhibitory systems in response to a stimulus, gives the individual the ability to generate appropriate responses that meet the demands of the environment. Reflecting its importance to brain functioning, the processes of synaptic neurotransmission are tightly regulated, including the proteins involved in synaptic vesicle formation, neurotransmitter release and subsequent vesicle endocytosis and recycling, neurotransmitter reuptake, the effects of the neurotransmitter itself on postsynaptic receptors, and subsequent signaling cascades and modulation of the signal communicated through the synapse. In addition, auxiliary subunits interact with the receptor-ligand complexes to modulate their properties. Furthermore, certain small proteins, such as trophins, hormones, and other peptides, can regulate the characteristics of the synaptic signal. All these diverse presynaptic, synaptic, and postsynaptic elements elegantly regulate the communication between neurons in the multiple and complex neuronal networks that make up the brain.

Abnormalities in the regulation of synaptic transmission play a role in the pathogenesis of many brain diseases. A consequence of this is a disruption to the equilibrium between excitation and inhibition in neuronal networks, which can lead to inappropriate neuronal firing and ultimately the generation of spontaneous, recurrent seizures. The spread of inappropriate neuronal firing to other neurons in the network is normally prevented by surrounding regulatory and modulatory synaptic mechanisms. This article reviews the different aspects of the regulation of synaptic transmission that may play a role in the pathogenesis of epilepsy, and how drugs can utilize these mechanisms to reduce the frequency and severity of epileptic seizures in people with epilepsy. Figure 1 summarizes the different proteins/regulatory subunits that are discussed and Table 1 defines the abbreviations used through the article.


Figure 1.  Schematic illustration of different elements involved in regulation of synaptic transmission. The arrows represent the path a synaptic vesicle follows from endocytosis to exocytosis. 1*, syndapin and dynamin are key proteins that modulate the synaptic vesicle endocytosis by pinching off the budding membrane into a synaptic vesicle ready to be filled by neurotransmitters. 2*, vesicular glutamate transporter (VGLUT) and vesicular GABA transporter (VGAT) help to fill the synaptic vesicle with the neurotransmitters glutamate and GABA, respectively. Synapsin I and II and SV2A are key proteins that modulate the synaptic vesicle exocytosis. 3*, the postsynaptic receptors include the ionotropic glutamate receptors, AMPA, NMDA, and kainate receptors. The seven transmembrane G-protein–coupled metabotropic receptor, mGluR, can be found both presynaptically and postsynaptically. The G protein is composed of α, β, and γ subunits. In addition, auxiliary subunits, like the TARPs, CNIH, Neto, DREAM, and Homer can interact with the receptor-ligand complexes to modulate their properties. 4*, the neuropeptides regulate the characteristics of the synaptic signal, with receptors that are located either presynaptically or postsynaptically. The receptors for ghrelin, somatostatin, NPY, and galanin are G-protein coupled. TrkB activation by BDNF causes phosphorylation of CREB and Egr3 to regulate NMDA and GABA receptor synthesis.

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Table 1.   Abbreviations used in the article
ABPAMPA-receptor binding protein
ADAR2Adenosine deaminase acting on RNA
AgRPAgouti-related protein
AMPAα-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ATPAdenosine triphosphate
BDNFBrain-derived neurotrophic factor
CaMKIICa2+/calmodulin-dependent protein kinase II
cAMPCyclic adenosine monophosphate
CKAMP44Cystine-knot AMPAR modulating protein
CNSCentral nervous system
CP-AMPACalcium permeable AMPA receptors
CREBcAMP response element binding protein
DGDentate gyrus
DREAMDownstream regulatory element antagonist modulator
Egr3Early growth response factor 3
EPSCsExcitatory postsynaptic currents
EREndoplasmic reticulum
GABAγ-Aminobutyric acid
GAERSGenetic absence epilepsy rats from Strasbourg
GalRGalanin receptor
GHSRGrowth hormone secretagogue receptor
GRIPGlutamate receptor interacting protein
iGluRIonotropic glutamate receptor
IPSCsInhibitory postsynaptic currents
KARKainate receptors
LTDLong-term depression
LTPLong-term potentiation
MAPKMitogen-activated protein kinase
mGluRMetabotropic glutamate receptors
mRNAMessenger ribonucleic acid
NMDA N-methyl-d-aspartate
NPYNeuropeptide Y
nRTReticular thalamic nucleus
PDZZonula occludens
PICK1Protein interacting with C-kinase 1
PKCProtein kinase C
PPPancreatic polypeptide
PSDPostsynaptic density
PSD-95Postsynaptic density-95
PYYPeptide YY
SAP-97Synapse-associated protein of 97 kDa
SEStatus epilepticus
SNAP-23Synaptosomal-associated protein 23
SOL-1Suppressor of lurcher
SV2ASynaptic vesicle protein 2A
SynDIG1Synapse differentially induced gene 1
TARPTransmembrane AMPA receptor regulatory protein
TLETemporal lobe epilepsy
TrkBReceptor tyrosine protein kinase B
VGATVesicular GABA transporter
VGCCVoltage-gated calcium channels
VGLUTVesicular glutamate transporter
WAG/RijWistar Albino Glaxo Rats from Rijswijk

Modulators of Synaptic Vesicle Formation, Release, and Recycling

  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Sustaining synaptic transmission depends upon the cycle of formation, release, and reformation of synaptic vesicles via membrane recycling processes of exocytosis and endocytosis (Heine, 2012). Multiple proteins are involved in these processes, such as synapsin, dynamin, syndapin, and synaptic vesicle proteins. Long-term changes in presynaptic morphology and synaptic vesicle recycling at hippocampal mossy fiber CA3 terminals of rats and mice after pilocarpine-induced status epilepticus (SE) have been described. The changes include alterations in the morphology of mossy fiber synaptic buttons, including increased size, number of release sites, and number of vesicles in the reserve pool and the readily releasable pool. These changes suggest that the morphologic changes are components of the response to increased activation that underlie enhanced transmitter release (Upreti et al., 2012). In agreement Goussakov et al. (2000) found an increase in glutamate release from the readily releasable pool and loss of paired-pulse facilitation, a presynaptic short term mechanism of synaptic plasticity, in the kainic acid model of temporal lobe epilepsy (TLE). In addition, number of active zones (characterized by synaptic vesicles in proximity to a presynaptic density, widening of the synaptic cleft, and asymmetry between presynaptic and postsynaptic densities), increased action potential–driven vesicular release, and enhanced vesicle endocytosis have been documented at the mossy fiber synaptic button in models of pilocarpine-induced SE, which persisted at least 1 month (Upreti et al., 2012). However, of the numerous proteins involved in vesicle release and recycling systems, only a few have to date been related directly to epileptogenesis, including synaptic vesicle protein 2A (SV2A), synapsin, dynamin, and syndapins (Qualmann et al., 1999; van Vliet et al., 2009; Raimondi et al., 2011).

Synaptic vesicle protein 2A

SV2A is the most abundant and widely expressed member of a family of membrane-bound glycoproteins found on synaptic vesicles. This family is encoded by three different genes: SV2A, SV2B, and SV2C (Janz & Sudhof, 1999; Janz et al., 1999). SV2A is the only member of the family expressed in γ-aminobutyric acid (GABA)ergic neurons (Bajjalieh et al., 1994), and has become of particular interest to the epilepsy field since it was discovered to be the target of binding of the antiepileptic drug levetiracetam (Lynch et al., 2004).

SV2A plays a role as a regulator of synaptic vesicle exocytosis and influences the calcium (Ca2+) homeostasis of synaptic vesicle constituents by regulating the expression and trafficking of the Ca2+-binding protein synaptotagmin (Yao et al., 2010), and influencing the presynaptic Ca2+ and adenosine triphosphate (ATP) concentrations (Janz et al., 1999; Yao & Bajjalieh, 2008; Wan et al., 2010). Studies on SV2A knockout mice have shown reduced evoked action potential–dependent transmitter release from inhibitory neurons (Custer et al., 2006; Chang & Sudhof, 2009). In addition, mice in which the function of both SV2A and SV2B has been knocked out showed an increase in Ca2+-dependent synaptic transmission (Janz et al., 1999). This led to the hypothesis that SV2A can regulate presynaptic Ca2+ release, and that the dysfunction of this protein could lead to Ca2+ accumulation during repeated action potential generation, ultimately resulting in increased neurotransmitter release and destabilization of neuronal circuits, facilitated by excitatory transmission and a concurrent attenuation of inhibition (Janz et al., 1999). SV2A expression is decreased throughout the hippocampus of patients with drug-resistant TLE with hippocampal sclerosis (van Vliet et al., 2009). Similarly, SV2A has been found to be decreased throughout the hippocampus of epileptic rats, particularly in the mossy fiber terminals in the latent and chronic epileptic phase post-SE (van Vliet et al., 2009). These data support the hypothesis that reduced expression of SV2A contributes to an increased epileptogenicity.

Drugs interacting with synaptic vesicle protein 2A

Levetiracetam has arguably been the most successful of the new-generation antiepileptic drugs introduced into clinical practice over the last two decades, with broad spectrum efficacy against a range of focal and generalized seizure types (De Smedt et al., 2007; Lo et al., 2011). Levetiracetam has a novel mechanism of action relative to that of the older antiepileptic drugs, in that it binds with high affinity to SV2A (Lynch et al., 2004) and inhibits presynaptic Ca2+ channels (Vogl et al., 2012). However, the exact mechanism by which levetiracetam inhibits seizures remains to be determined (Kaminski et al., 2009). Novel levetiracetam analogs, brivaracetam and seletracetam, also bind to SV2A (Bennett et al., 2007; von Rosenstiel, 2007). Both brivaracetam and seletracetam bind more potently to the SV2A than levetiracetam, and there is some evidence for superior efficacy in preclinical models (Matagne et al., 2009). However, it is uncertain whether this will translate into improved clinical effectiveness.


The synapsins are phosphoproteins that are highly expressed in presynaptic boutons, where they interact with small synaptic vesicles to regulate neuronal development, neurotransmission, and plasticity (Bogen et al., 2011). There are three different synapsin proteins: synapsin I (SynI), synapsin II (SynII), and synapsin III (SynIII). In general, SynI and SynII are more abundant in hippocampal and cortical excitatory synapses than in inhibitory synapses (Kielland et al., 2006). The synapsins have direct involvement in the regulation of synaptic vesicle dynamics. They control synaptic vesicle trafficking between the reserve pool and the readily releasable pool in a phosphorylation-dependent fashion (Chi et al., 2003; Baldelli et al., 2007; Messa et al., 2010). Synapsin binds the synaptic vesicle to the cytoskeleton, which prevents them from being trafficked to the presynaptic membrane. During an action potential, synapsins are phosphorylated by Ca2+/calmodulin–dependent protein kinase II (CaMKII), releasing the synaptic vesicles and allowing them to move to the presynaptic terminal and release neurotransmitter. Moreover, synapsins play a role in the final post-docking steps of exocytosis, including synaptic vesicle priming and fusion to the synaptic membrane (Hilfiker et al., 2005; Chiappalone et al., 2009). Knockout mice models of SynI, SynII, SynI/II, and SynI/II/III manifest an epileptic phenotype, indicating that synaptic vesicle cycling plays an important role in epileptogenesis (Etholm et al., 2011, 2012; Farisello et al., 2012). The different effects in these knockout models are complex and not fully understood. Of interest, the seizure phenotype varies depending on which isoform has been deleted. However, in general, the loss of synapsins disrupts the reserve pool of synaptic vesicles and enhances synaptic depression, which is seen more markedly in glutamatergic than in GABAergic synapses. This can result in an imbalance between synaptic excitatory and inhibitory transmission, both under conditions of basal electrical activity and of high-frequency stimulation, potentially leading to a hyperexcitable seizure-prone state (Farisello et al., 2012).

In humans, a missense mutation in the gene coding for SynI has been found as a cause of different epilepsy phenotypes in a four-generational family, with some affected members also having aggressive behavior, learning disabilities, or autism (Garcia et al., 2004). Recently, another missense mutation in the human SYN1 gene was identified in all affected individuals from a large French–Canadian family with epilepsy and autism spectrum disorders (Fassio et al., 2011). In addition, population genetic studies have identified single nucleotide polymorphisms in the human SYN2 gene that show an association with epilepsy in certain populations (Cavalleri et al., 2007; Lakhan et al., 2010).


The dynamins are a family of proteins with GTPase activity that are involved in endocytic vesicle formation. After the plasma membrane invaginates at the beginning of vesicular endocytosis, dynamin forms a helix that expands and twists around the neck of the new budding vesicle. As this process continues, dynamin tweaks the budding membrane into a synaptic vesicle, ready to be filled by neurotransmitters (Ramachandran, 2011). There are three subtypes of dynamin, each with different expression profiles. Dynamin 1 is expressed in the brain, with highest expression in the cortex, amygdala, striatum, and neuroendocrine cells (Faire et al., 1992). Dynamin 2 is expressed in most cell types in the body, including the brain. Dynamin 3 is highly expressed in the testis and also in the brain, heart, and lung (Cao et al., 1998; Ferguson & De Camilli, 2012).

At least two pathways by which dynamin regulates vesicle endocytosis have been identified: a quick, high capacity pathway that acts during intense neuronal activity, mediated by dynamin 1, and a low capacity pathway that is suppressed during stimulation but is gradually activated when stimulation ceases, mediated by dynamin 2 (Ferguson et al., 2007). Dynamin 1 becomes active only when an intense stimulus imposes a heavy burden on endocytosis and only as long as the stimulus persists. In dynamin 1 knockout mice, dynamin 3 is recruited into the synapses in a compensatory fashion; however, since its expression is much lower, dynamin 3 cannot cope with the demands imposed at high neuronal activity, resulting in decreased synaptic transmission efficiency (Ferguson et al., 2007).

Although there is currently no direct evidence linking the dynamin proteins to epilepsy in humans, a missense mutation in dynamin 1 has recently been found to cause the epilepsy phenotype in the “fitful” mouse model (Boumil et al., 2010). Dynamin-associated mechanisms have been suggested as a possible target for novel antiepileptic drugs, as it has been shown that inhibiting dynamin binding to syndapin with a peptide-based inhibitor produced an activity-dependent rundown in synaptic transmission. The peptide had no effect on synaptic transmission for 45 s, but after this delay it became progressively more inhibited, suggesting that this approach may be able to selectively inhibit the sustained neuronal firing that occurs during a seizure while allowing physiologic neurotransmission to occur normally (Anggono et al., 2006). The search for new drugs for epilepsy targeting endocytosis and other mechanisms associated with synaptic vesicle recycling is underway. There are ongoing pre-studies testing dynamin drugs in rodent models of seizures and epilepsy, including in our group, with proof of concept efficacy being demonstrated. The potential attractiveness of this approach is that the targeting of synaptic vesicle recycling may have selective effects to inhibit sustained neuronal firing, as occurs in a seizure that is highly dependent on synaptic vesicle endocytosis, while allowing normal physiologic neuronal firing to continue unaffected (Anggono et al., 2006).


Syndapins (Synaptic dynamin-associated proteins) are highly conserved Src-homology 3-domain–containing proteins. They interact with dynamin and several other vesicular trafficking proteins involved in vesicular endocytosis (Qualmann et al., 1999; Qualmann & Kelly, 2000). Mice that lack syndapin I show impairments in synaptic vesicle formation and synaptic transmission (Koch et al., 2011). The alterations in synaptic vesicle formation are explained by the close interplay between syndapin and dynamin (Ferguson et al., 2007). The syndapins bind to the three isoforms of dynamin, and in syndapin I knockout mice, the recruitment of dynamin was impaired (Koch et al., 2011). The alterations seen in synaptic vesicle size and endocytic mechanisms mimic those seen in the dynamin knockout mice models (Ferguson et al., 2007; Koch et al., 2011). Reduced evoked excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) amplitudes, and the stronger impairment of IPSCs, were especially shown with very high frequency stimulation in knockout syndapin mice (Andersson et al., 2008). Taken together, these defects led to an increased hippocampal network activity with lowered threshold for epileptiform discharges, strongly increased amplitudes of epileptiform discharges, as well as a much higher power of induced gamma oscillations, which in turn may lead to the generation of seizures (Clayton et al., 2009; Koch et al., 2011). In humans, syndapin I is found in the gene locus 6p21.3, which has been reported to be associated with genetic generalized epilepsy (Turnbull et al., 2005).

Postsynaptic Receptor Regulation

  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Neurotransmitters released presynaptically can bind to their postsynaptic receptors and activate downstream signaling cascades, the effects of which can be modulated by a vast array of auxiliary regulatory subunits. Regulators of postsynaptic neurotransmission ionotropic glutamate receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], N-methyl-d-aspartate [NMDA], and kainate receptors) and metabotropic glutamate receptors are discussed. The role of GABA receptors in the regulation of synaptic transmission is discussed in other articles in this supplement.

Glutamate receptors

The major excitatory neurotransmitter in the brain is glutamate. Glutamate receptors can be divided into two major groups based on the mechanism by which their activation gives rise to the postsynaptic currents: ionotropic and metabotropic, with several subtypes existing for each group. Due the vast array of different subtypes of glutamate receptors, a wide range of physiologic processes are regulated by these receptors. Excessive glutamate receptor activation has been linked to a number of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia, in addition to epilepsy (Sheldon & Robinson, 2007). Recent work has shed light on another level of modulation of glutamate receptors by regulatory proteins.

Ionotropic glutamate receptors

The ionotropic glutamate receptor (iGluR) family is divided into four distinct subgroups based on receptor pharmacology and structural homology, including the AMPA receptors (GluA1–GluA4), kainate receptors (GluK1–GluK5), NMDA receptors (GluN1, GluN2A–GluN2D, GluN3A, and GluN3B), and δ receptors (GluD1 and GluD2) (Dingledine et al., 1999). The iGluRs are tetramers with a binding site for glutamate on each subunit that assemble as dimer of dimers, and their composition can be homomeric or heteromeric (Traynelis et al., 2010).

AMPA receptors.  The majority of fast excitatory synaptic neurotransmission in the central nervous system (CNS) is mediated by glutamate activation of AMPA receptors (Dingledine et al., 1999). In addition to initiating neuronal firing, AMPA receptors also underlie aspects of synaptic plasticity (Dingledine et al., 1999), such as such as long-term potentiation (LTP) (Selcher et al., 2012). AMPA receptors are tetrameric assemblies of GluA1 to GluA4 subunits (Traynelis et al., 2010). Although homomeric receptors are functional, native AMPA receptors are believed to be heteromers. For example, in hippocampal pyramidal cells of mature rats, the most common subunit configurations are GluA1/GluA2 and GluA2/GluA3 (Dingledine et al., 1999; Traynelis et al., 2010). The permeability to Ca2+ ions of AMPA receptors is governed by the GluA2 subunit. The presence of a GluA2 subunit renders the channel impermeable to Ca2+ due to the posttranslational mRNA editing of a glutamine (Q) to an arginine (R) residue (Seeburg & Hartner, 2003). The majority of GluA2 subunits in the CNS are edited to the GluA2(R) form, thus the principal ions gated by these AMPA receptors are sodium (Na+) and potassium (K+) (Dingledine et al., 1999). Conversely, AMPA receptors lacking GluA2- or containing an unedited (Q form) of GluA2 are rendered permeable to Ca2+ ions (Sommer et al., 1991). This editing is catalyzed by the enzyme adenosine deaminase acting on RNA (ADAR2). This enzyme has also shown to edit the Kv1.1 potassium channel, conferring a loss in 4-aminopyridine sensitivity to kainic acid–induced seizures (Streit et al., 2011). The imbalance between AMPA receptors and CP-AMPA receptors has been related to epileptogenesis (Tanaka et al., 2000), the processes by which a normal brain becomes epileptic (McNamara et al., 2006). Krestel et al. (2004) showed in adult rat brains that seizure susceptibility is increased by the presence of the CP-AMPAR (GluA2[Q] receptors), and that these types of receptors play a role in circuit hyperexcitability. In addition, susceptibility to hypoxia-induced seizures occurs in the brain during developmental stages when there is an increased expression of CP-AMPA receptors. Consequently, perinatal hypoxia-induced seizures increase the expression of CP-AMPA receptors and the capacity for an AMPA receptor–mediated epileptogenesis (Sanchez et al., 2001). Moreover, studies have found a reduction in the GluA2 subunit in the amygdala, piriform cortex, and limbic forebrain in rats after amygdala kindling (Prince et al., 1995, 2000). Furthermore, decreased mRNA expression of GluA2 was found in the hippocampal CA1 region and dentate gyrus in rats experiencing pentylenetetrazol (PTZ) –induced seizures (Ekonomou et al., 2001). In the pilocarpine model of TLE, increased levels of CP-AMPAR were observed in the hippocampal membrane, which can contribute to the elevation of intracellular Ca2+ during recurrent burst firing. In addition, AMPAR–mediated currents became inwardly rectifying in the hippocampal CA1 neurons and dentate granule cells (Rajasekaran et al., 2012). Moreover, the R/G editing, another posttranslational modification, of the GluA2 subunit was found to be increased in the hippocampus and temporal cortex from patients with refractory epilepsy. The increased editing at the R/G site in the hippocampal tissue of epilepsy patients may enhance responses to glutamate (Vollmar et al., 2004). Furthermore, a mutation in the Gria4 gene, which codes for the GluA4 subunit, has been identified in C3H/HeJ mice, which exhibit spontaneous absence seizures (Beyer et al., 2008). This mutation results in decreased expression of GluA4, which is one of the main AMPA-receptor subunits expressed in the reticular thalamic nucleus (nRT), and the predominant subunit in corticothalamic neurons (Mineff & Weinberg, 2000). GluA4-containing receptors have the fastest desensitization rate to glutamate (Mosbacher et al., 1994). Therefore, reduced expression of GluA4 can increase the duration of response to excitatory input by glutamate. This event could in turn promote increased burst firing in reticular neurons enhancing circuit synchrony (Meeren et al., 2002).

AMPA receptors can interact with a variety of proteins in the postsynaptic membrane that function as auxiliary subunits and can modify their properties. The majority of these interactions occur through the cytoplasmic C-terminal tail of AMPA receptors, with proteins containing postsynaptic density-95 (PSD-95), discs large, zonula occludens (PDZ) domains, including glutamate receptor interacting protein (GRIP), AMPA-receptor binding protein (ABP), protein interacting with C-kinase 1 (PICK1), and synapse-associated protein of 97 kDa (SAP-97), or via non-PDZ domains (Srivastava et al., 1998; Dev et al., 1999; Kim & Huganir, 1999; Xia et al., 1999). Proteins that contain a PDZ domain that have been shown to interact with AMPA receptors include the transmembrane AMPA receptor regulatory proteins (TARPs; Chen et al., 2000), cornichon homologs (CNIH-2, CNIH-3; Schwenk et al., 2009), synapse differentially induced gene 1 (SynDIG1; Kalashnikova et al., 2010), and cystine-knot AMPAR-modulating protein (CKAMP44; von Engelhardt et al., 2010). These proteins differentially regulate AMPA-receptor channel gating and are involved in subunit folding, assembly, surface expression, and clustering and anchoring of AMPA receptors at synapses (Diaz, 2010; Jackson & Nicoll, 2011).

Transmembrane AMPA receptor regulatory proteins: TARPs are a family of proteins— including stargazin (γ2), γ3, γ 4, γ5, γ7, and γ8—with distinct and complementary expression patterns in both neurons and glia in the developing and mature CNS (Tomita et al., 2003; Kato et al., 2010). Stargazin (γ2) was the first TARP identified when a mutation in its gene (Cacng2) was found to cause the stargazer mouse, which manifests spontaneous absence-like seizures with generalized spike-and-wave discharges as well as having cerebellar ataxia (Letts et al., 1998). Stargazin was found to have structural homology to the γ1 subunit of the skeletal muscle voltage-gated Ca2+ channels (VGCCs) (Letts et al., 1998). Structurally, TARPs comprise four transmembrane domains and cytosolic amino- and carboxy-termini containing the PDZ domain. Despite the structural similarity with γ1, the TARPS are not expressed on the skeletal muscle and have minor or no effect on VGCCs (Tomita et al., 2003; Fukaya et al., 2005).

The TARPs regulate many different characteristics of the AMPA receptors such as AMPAR biogenesis, trafficking, anchoring AMPARs at the synapse, as well as modulating the channel kinetics. In the endoplasmic reticulum (ER), AMPA receptors are assembled by the formation of dimers and tetramers. TARPs associate with the tetrameric AMPAR to act as an auxiliary subunit permitting the efficient export of the AMPAR from the ER to the Golgi. Then, nPIST (a Golgi-enriched protein involved with trafficking of transmembrane proteins) binds to the C-terminal tail of stargazin in Golgi and assists the AMPAR–TARP complex to exit the Golgi and traffic it to the cell surface (Chen et al., 2000; Ziff, 2007). The AMPAR-TARP complex diffuses into the postsynaptic density PSD, where PSD-95 binds to the PDZ domain of the C-terminal tail of the TARP to anchor the complex at the synapse (Choi et al., 2002; Tomita et al., 2003, 2004; Ziff, 2007). Phosphorylation of TARPs by protein kinase C (PKC) and CaMKII is important in mediating AMPA-receptor synaptic transmission (Inamura et al., 2006). For example, stargazin phosphorylation increases AMPA-receptor synaptic trafficking, thereby establishing stargazin as critical in controlling synaptic strength (Tomita et al., 2005). Furthermore, TARPs can modify synaptic plasticity by affecting AMPA-receptor biophysical properties such as reduced receptor desensitization, slowed receptor deactivation rates, and increased recovery for desensitization (Priel et al., 2005).

Stargazer mice, which harbor a mutation in the stargazin gene that results in a decrease in expression of the stargazin protein, lack functional AMPA receptors in the cerebellum (Letts et al., 1998). In the thalamocortical synapses, AMPA receptors are reduced in the nRT, due to a reduction of GluA4 and GluA2/3 subunit expression (Barad et al., 2012). In contrast, the levels of AMPA receptors in the cortex remain unchanged, probably because stargazin is not the predominant TARP expressed in the cerebral cortex and the possible compensatory effect of the other TARPs expressed in the cortex (Tomita et al., 2003; Fukaya et al., 2005). In the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of genetic generalized epilepsy that manifests spontaneous absence seizures associated with generalized spike-and-wave discharges on electroencephalography (EEG), without any other neurologic deficit, stargazin expression is increased in the somatosensory cortex and thalamus (Powell et al., 2008). This increase in stargazin expression was also associated with an increase in the cortical membrane expression of AMPA-receptor subunits GluA1 and GluA2 (Kennard et al., 2011). The findings in these two rodent models illustrate that either a decrease or an increase in stargazin expression can be associated with an absence seizures phenotype, highlighting that perturbations in AMPA-mediated synaptic transmission, either positively or negatively, can result in an epileptic network.

Drugs that modulate AMPA receptors: Drugs that can inhibit AMPA-receptor activity have the potential to reduce excessive excitatory responses and may be promising future antiepileptic drugs (Meldrum & Rogawski, 2007; Rogawski, 2011). Perampanel, a noncompetitive and highly selective AMPA-receptor antagonist, is currently in phase III development as an adjunctive treatment for drug-resistant partial-onset seizures (Krauss et al., 2012). Parampanel also decreases intracellular Ca2+ concentration induced by AMPA-receptor activation, which would have the net effect of decreasing excitability (Hanada et al., 2011; Ceolin et al., 2012). Perampanel has been shown to have antiseizure effects in a broad range of rodent models, but showed no effect in the GAERS model, suggesting that it is less likely to be effective clinically against absence seizures (Hanada et al., 2011).

N-methyl-d-aspartate receptors.  NMDA receptors play a crucial role in excitatory neurotransmission regulation in the CNS. NMDA receptors are cationic channels permeable to Na+, K+, and Ca2+ (Perez-Otano & Ehlers, 2005). The Ca2+ influx through NMDA receptors is the critical factor that mediates many of its roles in health and disease (Cull-Candy & Leszkiewicz, 2004). The NMDA receptors are tetramers composed of different subunits: GluN1, GluN2A–GluN2D, and GluN3A–GluN3B (Traynelis et al., 2010). GluN1 is a necessary subunit of all NMDARs; genetic deletion of this subunit causes death in neonatal stages (Forrest et al., 1994). The C-terminus region of GluN1 regulates NMDAR trafficking and binding to proteins, including calmodulin, CaMKII, yotiao, alpha-actinin, tubulin, neurofilaments, and downstream regulatory element antagonist modulator (DREAM; Cull-Candy & Leszkiewicz, 2004; Horak & Wenthold, 2009).

Both GluN2A and GluN2B subunits are highly expressed in the cortex and hippocampus, where they are reported to control synaptic plasticity and metaplasticity (Monyer et al., 1994). Mutations in the GRIN2A gene, which codes for the human GluN2A, have been identified in patients with idiopathic epilepsy (Endele et al., 2010). Moreover, haplotypes of GRIN1, the gene encoding for the human GluN1 subunit, have been associated with infantile spasms, further indicating an involvement of NMDARs in epilepsy (Ding et al., 2010). Decreased GluN2B mRNA expression has been found in pyramidal neurons of TLE patients with hippocampal sclerosis, whereas an up-regulation of this subunit was found in pyramidal cells of nonsclerotic hippocampi from epileptic patients (Mathern et al., 1998).

Drugs that alter NMDA receptor properties: Felbamate was the first new-generation antiepileptic drug introduced in the 1990s, and it is highly effective against a broad range of seizure types (Sachdeo et al., 1992), but has had its clinical use severely limited following the discovery that it rarely results in the potential fatal adverse effects of aplastic anemia and liver failure (Pellock, 1999). Felbamate inhibits NMDA-evoked responses, preferentially in NMDA receptors containing GluN2B subunits, as well as potentiates GABA-evoked responses (Sofia, 1994).

Remacemide is a low-affinity noncompetitive antagonist of NMDA receptors (Subramaniam et al., 1996; Norris & King, 1997) but has also been shown to inhibit sustained repetitive firing in cultured neurons by blocking voltage-activated Na+ channels (Garske et al., 1991). Remacemide is effective against a broad range of animal seizure models (Palmer et al., 1991). However, clinical trials of remacemide have overall shown relatively disappointing efficacy (Cramer et al., 1994; Brodie et al., 2002; Wesnes et al., 2009). Other potential new antiepileptic drugs in development that have been found to have effects in at least part by modulating NMDA-receptor action include losigamone (Srinivasan et al., 1997), which also reduces potassium-evoked release of glutamate and aspartate from cortical slices (Draguhn et al., 1997) and enhances GABAergic synaptic transmission (Dimpfel et al., 1995). Huperzine A, which shows protective activity against partial seizures in animal models (Schneider et al., 2009), is an NMDA-receptor antagonist (Zhang et al., 2002) and can reduce glutamate-induced toxicity (Ved et al., 1997).

Kainate receptors.  Kainate receptors (KARs) are members of the iGluR receptor family that show distinctive characteristics. Unlike AMPA and NMDA receptors, KARs are not predominantly found in excitatory postsynaptic complexes (Contractor & Swanson, 2008). Instead, KARs act as modulators of synaptic transmission and neuronal excitability. Noticeably, they link to metabotropic (G-protein–mediated) signaling pathways in addition to operating as ionotropic receptors (Rodriguez-Moreno & Lerma, 1998). KARs are distributed throughout the brain pre- and postsynaptically and are involved in the regulation of activity of synaptic networks by postsynaptic depolarization at a subset of excitatory synapses, in presynaptic regulation of neurotransmitter release, in presynaptic modulation of both excitatory and inhibitory transmission, in refinement of synaptic strength during development, and in enhancement of neuronal excitability (Contractor et al., 2011). The KARs are tetramers formed by combinations of low-affinity, GluK1–GluK3, and high affinity, GluK4–GluK5 subunits (Collingridge et al., 2009). All subunits contribute to the formation of the ionic pore and each one contains a glutamate-binding site (Fisher & Mott, 2011).

It is notable that in a rat model of TLE, aberrant synaptic kainite receptors dramatically expand the temporal window for synaptic integration in dentate granular cells. This introduces a change in the input–output operation of dentate granule cell that switches their firing from a sparse to an abnormal sustained and rhythmic mode (Artinian et al., 2011). Moreover, in the entorhinal cortex, both GluK1 and GluK2 have been implicated in regulating the network oscillations and enhancing both glutamate and GABA release in this critical area for epileptogenesis in mesial TLE (Bartolomei et al., 2005; Chamberlain et al., 2012).

Drugs that modulate kainate receptors: There are no antiepileptic drugs in clinical practice, or in advanced clinical development, that have been shown to have effects primarily on kainate receptors. However, the experimental compound, LY293558, which inhibits GluK1-containing kainate receptors, has been shown to be effective in reducing the duration of SE in rats (Figueiredo et al., 2011). This drug is a nonselective antagonist, having effects on kainate and AMPA receptors (Alt et al., 2006; Jane et al., 2009).

Metabotropic glutamate receptors

The family of metabotropic glutamate receptors (mGluRs) are composed of eight receptor subtypes, grouped into three different families according to their amino acid homology, pharmacologic properties, and G-protein coupling (Conn & Pin, 1997). In general, the mGluRs are found preferentially in presynaptic terminals, where they negatively regulate neurotransmitter release (Ferraguti & Shigemoto, 2006). The exception are the group I mGluRs, which are found predominantly in the periphery of the postsynaptic density, where they generate excitatory responses and regulate mechanisms of synaptic plasticity (Ferraguti et al., 2008). Group I mGlu1Rs, can be activated with repetitive high-frequency stimulation of corticothalamic afferents (Turner & Salt, 2000; Hughes et al., 2002). When activated, these receptors can modulate the excitability of thalamic relay cells in the relay nuclei (Turner & Salt, 1998; Alexander & Godwin, 2006a; Alexander et al., 2006). In the Wistar Albino Glaxo Rats from Rijswijk (WAG/Rij) rat model of genetic generalized epilepsy that exhibits spontaneous absence seizures, a reduction of mGlu1-receptor expression in the thalamus was correlated with seizure expression (Ngomba et al., 2011). Younger WAG/Rij rats that are not having absence seizures did not show reduction in mGlu1-receptor expression of spike and wave discharges. In addition, activation of mGlu1 receptors by agonists confers a protective effect against the development of seizures (Ngomba et al., 2011). In contrast, the group II mGluRs modulate the inhibitory circuitry of the thalamus via a GABAergic mechanism. This inhibition occurs in the thalamic relay cells, both presynaptically and postsynaptically (Salt & Eaton, 1995; Salt & Turner, 1998; Turner & Salt, 2003). Furthermore, the activation of the group II mGluRs can cause presynaptic inhibition of the corticothalamic input onto the cells of the relay and nRT of the thalamus, potentially reducing the excitatory cortical drive onto GABAergic cells (Turner & Salt, 2003; Alexander & Godwin, 2005). Activation of the group III of mGluRs has been shown to reduce GABAergic inhibitory responses within the thalamus by inhibiting the corticothalamic input onto thalamic relay cells, mediated by activation of mGlu7 and mGlu8 receptors (Turner & Salt, 2003; Kogo et al., 2004).

Metabotropic glutamate receptors regulatory proteins.  Homer proteins (Homer 1, 2, and 3) are a family of scaffolding proteins found to regulate mGluR 1 and mGluR5 function and to facilitate coupling to effectors such as the inositol triphosphate receptor (Shin et al., 2003; Klugmann et al., 2005; Kammermeier & Worley, 2007) they are also found to be up-regulated in various CNS disorders including epilepsy (Potschka et al., 2002). Of interest, expression of Homer1a is induced during intense neuronal activities like LTP, seizures, and synaptogenesis (Kato et al., 1997). In addition, expression of Homer1a is augmented in various animal models of TLE, including the pilocarpine-induced SE and amygdala kindling models (Potschka et al., 2002; Avedissian et al., 2007), and has been considered to reduce seizure susceptibility in cortical pyramidal neurons by dampening neuronal excitability (Sakagami et al., 2005).

Metabotropic glutamate receptor modulating drugs.  Subtype-selective mGluR ligands are under preclinical and early clinical development for the treatment of neurologic and psychiatric disorders, including epilepsy, in particular because of the properties of mGluR to modulate the excitability of thalamic relay cells (Alexander & Godwin, 2006b; Govindaiah & Cox, 2006). SYN119, a mGluR1 enhancer, was found to reduce spontaneous spike and wave discharges in WAG/Rij rats (Ngomba et al., 2011).

Neuropeptide Modulators of Synaptic Neurotransmission

  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

The neuropeptides such as neuropeptide Y (NPY), somatostatin, ghrelin, and galanin, act as regulators of diverse synaptic functions and occur concomitantly with the classic neurotransmitters (Brain & Cox, 2006). They are short peptides of 3–100 amino acid residues long, with a less complex three-dimensional structure than proteins (Portelli et al., 2012). The majority of the neuropeptide receptors are members of the G-protein–coupled receptor family. Several neuropeptides and their receptors have been implicated in the pathogenesis of epilepsy, mostly by regulating the classical neurotransmitters systems, either by modifying the release of neurotransmitters or by regulating the effects of their activated receptors. This review will focus on the effects of systemic neuropeptide modulators rather than small molecule/peptide modulators such as adenosine (Boison, 2012; Moschovos et al., 2012).

Neuropeptide Y

NPY is a member of a neuropeptide family, which comprises NPY, peptide YY (PYY), and pancreatic polypeptide (PP) (Cabrele & Beck-Sickinger, 2000). NPY is a 36-amino acid peptide that is abundantly expressed in GABAergic interneurons of the mammalian CNS, with highest expression seen in the cerebral cortex, dentate hilus, striatum, the nRT, and the arcuate nucleus of the hypothalamus. NPY acts as a neurotransmitter that is synthesized and released by neurons (Gehlert, 1994; Pedrazzini et al., 2003). In the CNS, NPY acts to enhance inhibitory neurotransmission, and to dampen excitatory neurotransmission (Bacci et al., 2002). NPY has been shown to have antiepileptic effects in a number of models of acquired and genetic epilepsy (Cabrele & Beck-Sickinger, 2000; Tu et al., 2005; Noe et al., 2008; van Raay et al., 2012). NPY has been shown to be up-regulated in the temporal lobe from patients who have had resective surgery performed for chronic drug-resistant epilepsy (Furtinger et al., 2001), as well as in the hippocampus, dentate gyrus, and cortex from seizure/epilepsy animal models including electroshock-evoked seizures, pilocarpine-induced SE, pentylenetetrazol (PTZ)–induced seizures, kindling, and after electrically induced SE (Vezzani et al., 1996; Poulsen et al., 2002; Tu et al., 2005; Cardoso et al., 2010). Work from our group has also demonstrated that NPY has potent antiepileptic effect in the GAERS model of genetic generalized epilepsy (Stroud et al., 2005; Morris et al., 2007; van Raay et al., 2012). This suggests that NPY may act as an endogenous antiepileptic factor. Consistent with this finding, it has been shown that rats that have been injected bilaterally into the hippocampi with an adenoassociated viral vector to overexpress NPY are resistant to epileptogenesis induced by electrical kindling and SE (Richichi et al., 2004; Noe et al., 2009).

NPY signals through identified Y1, Y2, Y4, and Y5 receptors that couple to G-proteins, inhibiting adenylate cyclase and thus decreasing intracellular Ca2+ levels (Baraban, 2004; Walther et al., 2011). The receptors Y1R and Y5R bind preferentially to NPY, whereas Y4Rs have a high affinity for PP, and Y2R binds NPY and PYY with similar affinities (Cabrele & Beck-Sickinger, 2000; Guo et al., 2002; Fetissov et al., 2004; Merten & Beck-Sickinger, 2006; Lindner et al., 2008). Y1Rs are mainly expressed postsynaptically in the hippocampus, cerebral cortex, thalamus, and amygdala, and act to increase synaptic inhibition (Widdowson, 1993; Cabrele & Beck-Sickinger, 2000). Y5Rs are expressed postsynaptically in the hippocampus and hypothalamus, and like the Y1R, acts to increase synaptic inhibition (Guo et al., 2002). In contrast, Y2Rs are expressed presynaptically in the hippocampus, thalamus, hypothalamus, and cerebral cortex (Widdowson, 1993; Cabrele & Beck-Sickinger, 2000). Due to the presynaptic localization of NPY, it suppresses the release of neurotransmitters, in particular glutamate, thereby dampening excitatory neurotransmission (El Bahh et al., 2005). Studies investigating which NPY receptor subtypes are most important in mediating its antiepileptic actions have produced conflicting results, with work using models of acquired limbic epilepsy mostly implicating either Y1R or Y5R (Baraban, 1998; Marsh et al., 1999; Vezzani et al., 2000), whereas work in the GAERS model primarily implicates the Y2Rs (Morris et al., 2007).

There are many studies demonstrating the efficacy of NPY against a broad range of rodent models of both focal and generalized epilepsy when administered directly into the brain or cerebrospinal fluid (Marksteiner et al., 1989; Erickson et al., 1996; Kofler et al., 1997; Vezzani et al., 1999; Reibel et al., 2001; Noe et al., 2008, 2009; Sorensen et al., 2009). Selective NPY receptor antagonists have been developed with the aim of being new treatment for a variety of conditions including anxiety, sleep disorders, eating disorders, in addition to epilepsy (Ortiz et al., 2007; Wiater et al., 2011; Wu et al., 2011; van Raay et al., 2012). However, the barriers to clinical development have been developing compounds that are orally active, have sufficiently long half-life, and cross the blood–brain barrier (Meurs et al., 2007). One potential approach to overcome these barriers is to use viral-based gene therapy, focally administered into epileptogenic brain regions that selectively up-regulate NPY expression. Such an approach using NPY-containing adenoassociated virus vectors has shown proof-of-concept efficacy in several rat models of epilepsy (Richichi et al., 2004; Noe et al., 2008; Jovanovska et al., 2011).


Ghrelin is a 28 amino acid hunger-stimulating peptide mainly produced by the neurons in the hypothalamus and by the X/A-like cells of the oxyntic stomach mucosa (Camina et al., 2003). Ghrelin plays a significant role in a variety of physiologic processes such as appetite regulation, metabolism, LTP, and cognition (Wu & Kral, 2004; Atcha et al., 2009). Ghrelin binds to the G-protein–coupled growth hormone secretagogue receptor (GHSR1a), which is expressed at high density in the hippocampus, hypothalamus, and pituitary (Camina, 2006; Portelli et al., 2012). Activation of the ghrelin receptor leads to increased activity of NPY/AgRP (agouti-related protein) neurons, presynaptic release of NPY, as well as an increased rate of GABA secretion in hypothalamic slice preparations (Cowley et al., 2003).

Studies from animal models have implicated ghrelin in epileptogenesis. Intraperitoneal injections of ghrelin delayed or prevented the development of PTZ-induced seizures in rats (Obay et al., 2007). Portelli et al. found that ghrelin release desensitizes the GHSR, and that this interaction leads to the attenuation of limbic seizures induced by pilocarpine in vivo and epileptiform activity in vitro. In contrast, another group found that ghrelin was unable to prevent seizures induced by kainic acid or pilocarpine. This group also found that des-acyl ghrelin, which accounts only for about 10% of the circulating ghrelin, can be beneficial in limbic seizures (Biagini et al., 2011). These contrasting results raise questions about the specific role of ghrelin in epilepsy and highlighted the need for further studies to address this discrepancy.


Somatostatin is a neuropeptide produced by the neuroendocrine neurons of the periventricular nucleus of the hypothalamus and is involved with the regulation of the endocrine system and affects neurotransmission and cell proliferation (Viollet et al., 2008). Somatostatin binds with high affinity to G-protein–coupled somatostatin receptors, SST1, SST2A, SST2B, SST3, SST4 and SST5 (Patel, 1999). Somatostatin secreting neurons are present in a variety of brain areas, including the mediobasal hypothalamus, median eminence, amygdala, preoptic area, hippocampus, striatum, cerebral cortex, olfactory regions, and the brainstem (Epelbaum et al., 1994; Gulyas et al., 2003; Tomioka et al., 2005). The extensive expression of somatostatin throughout the brain and the large number of SST receptor subtypes allows somatostatin to affect a diverse array of physiologic functions (Viollet et al., 2008). The regulatory effects of somatostatin are mostly presynaptic by interacting with the receptors SST1, SST2, SST4, and SST5 (Baraban & Tallent, 2004). On the other hand, most of the neurotransmitter-like effects of somatostatin are mediated by activation of the SST2 receptor (Viollet et al., 2008). Changes in expression of somatostatin and its receptors in the hippocampus have been reported in a variety of animal models of epilepsy. A decrease in SST2 receptor expression in the outer molecular layer of the hippocampus was observed following repeated seizures induced by amygdala kindling and kainate animal models of TLE (Binaschi et al., 2003). Furthermore, a progressive decrease in SST2A receptors and a progressive increase in somatostatin immunoreactivity was observed in the outer molecular layer of the dentate gyrus after repeated seizures elicited by hippocampal kindling (Csaba et al., 2004). In addition, a loss of somatostatin-expressing inhibitory neurons resulting in reduced granule cell inhibition has been reported after pilocarpine-induced SE (Kobayashi & Buckmaster, 2003). A decrease in SST2 receptor immunoreactivity and mRNA expression in the CA1 and CA3 regions of the hippocampus has been reported in patients with temporal lobe epilepsy with hippocampal sclerosis, suggested to be due to neuronal loss (Csaba et al., 2005). In contrast, in the dentate gyrus, SST2 mRNA was strongly up-regulated, and SST2 binding was increased in the inner molecular layer but robustly decreased in the outer molecular layer.


Galanin is a neuropeptide that is widely expressed throughout the brain and spinal cord and binds to three different G-protein–coupled receptors, GalR1, GalR1 and GalR3 (Mitsukawa et al., 2010). Activation of galanin receptors results in inhibition of presynaptic glutamate release, via a mechanism involving ATP-dependent K+ channels, which in turns lead to membrane hyperpolarization, a process furthermore enhanced by the additional effect of galanin to directly close VGCC (Zini et al., 1993; Mazarati et al., 2000). It is notable that galanin does not alter the inhibitory tone and has no effect on GABA release in the hippocampus (Zini et al., 1993; Mazarati & Lu, 2005). Moreover, activation of GalR2 can promote plastic reorganization in the hippocampus, and neuronal viability and survival in response to seizures (Mazarati et al., 2004). Galanin and GalR agonists have been shown to have antiseizure effects in a variety of animal models (Floren et al., 2005; Mazarati & Lu, 2005; Mazarati et al., 2006). GalR1 knockout mice exhibit spontaneous seizures and a reduced inhibition in the hippocampus (McColl et al., 2006). Whereas, GalR2 knockout mice showed no differences compared to wild-type controls in the latency to seizures induced by PTZ or flurothyl (Gottsch et al., 2005).

Saar et al. synthesized galnon, the first nonpeptide low–molecular-weight GalR1 and GalR2 agonist (Saar et al., 2002; Floren et al., 2005). Systemic administration of galnon showed potent anticonvulsant effects on PTZ-induced seizures and inhibited perforant path stimulation-induced SE in rats (Saar et al., 2002). Galmic, another GalR agonist, has also shown positive effects in PTZ-induced seizures and in SE models in rats (Bartfai et al., 2004). NAX 5055 (Gal-B2), a GalR agonist that shows high affinity for GalR1 and GalR2, has been shown to have anticonvulsant activity in three models of epilepsy including the 6-Hz seizure model, the Frings audiogenic seizure-susceptible mouse, and the corneal kindled mouse model of partial epilepsy (Bulaj et al., 2008; White et al., 2009). Moreover, in the hippocampal kindling model of TLE, NAX 5055 reduces the seizure score without affecting the afterdischarge duration (Bialer et al., 2010). In addition, the GalR2 preferred analogs, NAX 306-1 and NAX 1205-1 display activity in the 6-Hz seizure model when systematically administered (Bialer et al., 2010).

Brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that binds with high affinity to the receptor tyrosine protein kinase B (TrkB), which is coupled to various signaling pathways including mitogen-activated protein kinase (MAPK)/PKC, phosphatidylinositol 3-kinase, and phospholipase C (Kaplan & Miller, 2000). BDNF has wide-ranging effects during development, including regulating neuronal morphology and synaptogenesis, plus it exhibits neuroprotective effects in diverse areas of the CNS (Stansfield et al., 2012). Both BDNF and TrkB have a widespread distribution in the CNS (Hofer et al., 1990). BDNF has been implicated as a potential therapeutic target for TLE. Importantly, high levels of expression are found in cell bodies and axons in areas associated with seizure susceptibility, such as hippocampus and entorhinal cortex (Wetmore et al., 1990). The involvement of BDNF in epileptogenesis is complex. In the kainic acid/pilocarpine-induced SE, kindling, PTZ, and tetanus seizure animal models, the seizures cause a prominent increase in the expression of BDNF in the brain, in particular the hippocampus (Zafra et al., 1990; Ernfors et al., 1991; Isackson et al., 1991; Humpel et al., 1993; Nibuya et al., 1995; Schmidt-Kastner et al., 1996; Liang et al., 1998). Acute administration of BDNF into the CA3 of the hippocampus, the dentate gyrus, and medial entorhinal cortex, produces neuronal hyperexcitability (Messaoudi et al., 1998; Binder et al., 2001; Kobayashi & Buckmaster, 2003). In fact, epileptogenesis has been shown to be promoted by an increase in BDNF and BDNF-mediated activation of the TrkB in the hippocampus in mice after intrahippocampal injections of kainic acid (Heinrich et al., 2011). Studies in patients with drug-resistant TLE with hippocampal sclerosis have found an increase in BDNF mRNA expression in the hippocampus compared with those without hippocampal sclerosis (Wang et al., 2011). BDNF has been reported to regulate synaptic transmission by a variety of mechanisms including increasing NMDA currents in human patients with TLE and hippocampal sclerosis and animal hippocampal slices and attenuating inhibition on GABAergic postsynaptic cells by down-regulating chloride transport (Wang et al., 2011).

Summary and Conclusions

  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Disturbances in synaptic transmission, in particular to the balance between excitatory and inhibitory synapses, play a role in the pathogenesis of seizures and epilepsy. Such disturbances can affect almost any of the many different components of synaptic transmission, including postsynaptic and presynaptic receptors and their modulators, neuropeptide modulators, and the machinery of synaptic vesicle formation, release, and recycling. The processes of synaptic transmission are also targets for therapies for epilepsy, including many antiepileptic drugs currently in use in clinical practice as well as novel therapies under development. However, the complex processes regulating synaptic transmission in health and disease are still incompletely understood. Further advancement in our understanding of these critical processes is likely to lead to identification of new targets for the development of novel treatment approaches with potential to address the considerable treatment gaps that remain for many patients with epilepsy, in particular drug-resistant epilepsies and the lack of disease-modifying therapies (Galanopoulou et al., 2012).


  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Pablo Miguel Casillas-Espinosa was funded by a Melbourne Research Scholarship and Kim Powell from a Project Grant (#628723) from the NH&MRC.


  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

TJO has received research support from pharmaceutical companies that market antiepileptic drugs, specifically UCB Pharma, Sanofi-Adventis, Janssen-Cilag, Novartis, and SciGen. He has served on the Medical Advisory Boards for UCB Pharma, Janssen-Cilag, and GSK, and he has received honoraria for talks from UCB Pharma, Sanofi-Adventis, and SciGen. The other authors have no conflicts to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.


  1. Top of page
  2. Summary
  3. Modulators of Synaptic Vesicle Formation, Release, and Recycling
  4. Postsynaptic Receptor Regulation
  5. Neuropeptide Modulators of Synaptic Neurotransmission
  6. Summary and Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References
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