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Keywords:

  • Generalized epilepsy;
  • Genetic absence epilepsy rats from Strasbourg;
  • Somatosensory cortex;
  • Thalamocortical circuit

Summary

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Purpose:  Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocortical circuit that NPY acts to suppress seizures in genetic absence epilepsy rats from Strasbourg (GAERS).

Methods:  In conscious freely moving GAERS, NPY was administered via intracerebral microcannulae implanted bilaterally into one of the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), the primary motor cortex (M1), caudal nucleus reticular thalamus (nRT), or ventrobasal thalamus (VB). Animals received vehicle and up to three doses of NPY, in a randomized order. Electroencephalography (EEG) recordings were carried out for 30 min prior to injection and 90 min after the injection of NPY or vehicle.

Key Findings:  Focal microinjections of NPY into the S2 cortex suppressed seizures in a dose-dependent manner, with the response being significantly different at the highest dose (1.5 mm) compared to vehicle for total time in seizures postinjection (7.2 ± 3.0% of saline, p < 0.01) and average number of seizures (9.4 ± 4.9% of saline, p < 0.05). In contrast NPY microinjections into the VB resulted in an aggravation of seizures.

Significance:  NPY produces contrasting effects on absence-like seizures in GAERS depending on the site of injection within the thalamocortical circuit. The S2 is the site at which NPY most potently acts to suppress absence-like seizures in GAERS, whereas seizure-aggravating effects are seen in the VB. These results provide further evidence to support the proposition that these electroclinically “generalized” seizures are being driven by a topographically restricted region within the somatosensory cortex.

Neuropeptide Y (NPY) is a 36–amino acid residue member of the pancreatic polypeptide family. Five G protein–coupled NPY receptors have been cloned, which are linked to the inhibition of adenylate cyclase and regulation of intracellular calcium. NPY is colocalized with several other neurotransmitters and is a critical inhibitor of neuronal excitability. Evidence for the antiepileptic action of NPY in acquired limbic epilepsies has been steadily accumulating from animal studies in vivo (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) and in vitro (Greber et al., 1994; Marsh et al., 1999), as well as in human studies (Patrylo et al., 1999; Takahashi et al., 1999; Furtinger et al., 2001; Thom et al., 2009). However less work has been done on the effect of NPY in generalized, thalamocortical-based epilepsies, which can respond differently to certain antiepileptic drugs (AEDs) when compared with the limbic epilepsies (Perucca et al., 1998; Stroud et al., 2005; Liu et al., 2006). Our group has shown that NPY injected intracerebroventricularly (i.c.v.) potently suppresses generalized absence-type seizures in the genetic absence epilepsy rats from Strasbourg (GAERS) (Stroud et al., 2005; Morris et al., 2007), with Y2 receptors being most important in mediating this effect (Morris et al., 2007).

Absence seizures are one of the most common types of seizures seen in patients with idiopathic generalized epilepsies, occurring in a number of different syndromes, in particular childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME) (Commission on Classification and Terminology of the International League Against Epilepsy 1981). Absence seizures are characterized by recurrent nonconvulsive episodes of loss of awareness and responsiveness, commonly accompanied by minor motor manifestations but without loss of postural tone. The electroencephalography (EEG) recording during absence seizures shows bihemispheric, synchronous, generalized spike-and-wave discharges (SWDs) at approximately three cycles per second, which start and end abruptly on an otherwise normal background EEG. GAERS are a well-characterized rat model of idiopathic generalized epilepsy with spontaneous absence-type seizures that are accompanied by generalized SWDs that are morphologically similar to absences seizures in humans, except they have a faster cycle frequency (i.e., 6–8 Hz. compared with 3 Hz) (Danober et al., 1998; Powell et al., 2009). Furthermore, the seizures in GAERS have a pharmacologic response profile similar to those of human absence seizures (Danober et al., 1998). The neurophysiologic basis of absence seizures in GAERS, and in humans, is sustained oscillatory firing within the thalamocortical circuit (Danober et al., 1998). The circuit consists of reciprocally innervated excitatory corticothalamic and thalamocortical glutaminergic neurons in the cortex and ventrobasal thalamus (VB), and γ-aminobutyric acid (GABA)ergic inhibitory neurons in the thalamic reticular nucleus (nRT) and the cortex (Danober et al., 1998). Focal administration of AEDs into different areas of the thalamocortical circuit can suppress or aggravate the seizures in GAERS (Gurbanova et al., 2006; Liu et al., 2006; Gulhan Aker et al., 2006; Polack & Charpier, 2009; Polack et al., 2009).

This study aimed to investigate the site within the thalamocortical circuit that NPY most potently acts to exert its anti–absence seizure effect in GAERS. The effects on spontaneous seizures in freely moving rats were measured of focal microinjections of NPY into key regions of the circuit: the primary somatosensory cortex (S1), the secondary somatosensory cortex (S2), the (VB), or the caudal nRT.

Materials and Methods

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Animals

Thirty-eight adult male GAERS were bred at the Ludwig Institute for Cancer Research at the Royal Melbourne Hospital, The University of Melbourne. At the time of the beginning of the experiments, all rats were at least 4 months old, with a mean weight of 292 g ± 7 (standard error of the mean [SEM]), and all expressed spontaneous absence seizures with SWDs on the EEG recording. Rats were individually caged after surgery with ad libitum food and water on a 12 h dark/light cycle in a room maintained at 22°C. Experiments were approved by the animal ethics committee of the Ludwig Institute of Cancer Research/Department of Surgery, The University of Melbourne, project number 2004.011, and followed the National Health and Medical Research Council Guidelines to promote the wellbeing of animals used for scientific purposes.

Surgery

Ketamine/xylazine (75 mg/kg ketamine and 10 mg/kg xylazine, Lyppard) mixture was administered into the intraperitoneal (i.p) region to induce general anesthesia. Once the animal was fully anesthetized it was secured into a digital stereotaxic frame (Stoelting, Kiel, WI, U.S.A.) and four to six burr holes were made in the skull by a small hand drill (1.4 mm Easy Etch Engraver, Arlec Australia, Blackburn North, Victoria, Australia). Each animal received four extradural electrodes: two in the frontal bone and two in the partial bone about equal distance away from the mid suture.

For the focal intracerebral injections, rats were implanted with two guide cannulae with injection needles (Plastics One, Roanoke, VA, U.S.A.). The cannulae were inserted bilaterally under stereotaxic guidance, as described previously (Lohman et al., 2005), into one of the following regions (anteroposterior [AP] and mediolateral [ML] distances were measured from bregma and dorsoventral [DV] measurements from dura): VB (n = 9 rats) −3.5 mm AP, ±2.6–2.8 mm ML; the caudal nRT) (n = 6 rats) −3 mm AP, ±3.6 mm ML and 5.8 mm DV; S1 (n = 6 rats) +0.2 mm AP, ±3.6 mm ML and 1.3–1.6 mm DV; S2 (n = 6 rats) +0.2 mm AP, ±5.8 mm ML and 2.5–2.75 mm DV; and primary motor cortex (M1) (n = 8 rats) +2.7 mm AP, ±2.6 mm ML and 1.4–1.8 mm DV.

Electrodes and cannulae were secured in place using dental cement (Vertex-Dental, Zeist, The Netherlands). While cement was setting 1 ml of saline (NaCl 0.9%) was administered subcutaneously (s.c.) and carprofen (5 mg/kg, Pfizer, New York, NY, U.S.A.) was injected i.p to prevent dehydration and pain relief, respectively. NPY injections commenced 1 week postsurgery. Following surgery, a regimen of daily handling of the rats was implemented to facilitate handling during experiments.

NPY injections and EEG recordings

Neuropeptide Y (NPY) (Auspep, Tullamarine, Victoria, Australia) was diluted with saline (NaCl 0.9%), aliquoted, and stored at −20°C. Rats with bilateral intracerebral cannulae received three doses of NPY and a vehicle (saline): The concentration of the NPY administered in four different regions was the same (i.e., 0.15, 0.5, 1.5 mm); however, the volume injected was larger for the cortical regions (1 μl) than for the thalamic regions (0.2 μl) because of the difference in their sizes. The following numbers of rats were studied for each region: VB = 9, nRT = 6, S1 = 6, S2 = 6, and M1 = 8. For the i.c.v. injections each rat (n = 5) received 2 μl NPY (1.5 mm) or vehicle (0.9% saline) as per our previous studies (Morris et al., 2007).

A baseline EEG recording of 45 min was acquired to confirm that rats had sufficiently frequent seizures (i.e., at least one seizure every 2 min). For the intracerebral drug injections, rats were removed from their cage, wrapped in a towel, and held while drugs were infused over 10 min using two programmable infusion pumps (Aladdin, World Precision Instruments, Sarasota, FL, U.S.A.) with 5 μl Hamilton syringe (World Precision Instruments) Rats were allowed to recover in their home cage for 15 min after which a 90-min postinjection EEG recording was obtained. During this time rats were monitored and prevented from falling asleep. Food intake was measured during the 90-min postinjection. Injections were performed at the same time of day for each animal, with at least 2 days between injections. The order of the treatments was randomized for each experiment. The recordings and drug microinjections were performed in a quiet room with the animals free to move about in their home cages.

EEG analysis was performed off-line by an operator blinded to the treatment who manually noting the seizure start and stop time (32 channel series e-series, Compumedics Limited, Melbourne, Victoria, Australia), as in our previous studies (Stroud et al., 2005; Morris et al., 2007). Seizure parameters quantified were total time in seizure during the 90-min postinjection, number of seizures per minute, and average seizure duration. The effect of the injections on mean SWD cycle frequency (instantaneous spike frequency) during the seizures was examined following the highest concentration NPY injections (1.5 mm) versus saline injections using Clampex 10 software (Molecular Devices, Sunnyvale, CA, U.S.A) by an operator blinded to the treatment: M1, n = 6; S2, n = 3; nRT, n = 5; and VB, n = 5. Up to 10 seizures were analyzed over a 30-min period starting 15-min post-NPY or saline injection. An effect on SWD cycle frequency on the seizures following the 1.5 mm NPY injections into the S1 region could not be included due to an inadequate number of analyzable seizures recorded.

Animal sacrifice, tissue collection, and documentation of site and extent of diffusion of the focal intracerebral injections

At the end of the experimental period, each animal was euthanized with a lethal dose of pentobarbitone sodium (pentobarbital 325 mg, i.p.; Virbac Animal Health, Milperra, NSW, Australia). To confirm correct bilateral cannulae placement; intracerebral rats received the same volume of methylene blue dye as they had been given for the NPY/saline injections (i.e., 1 μl for cortical and 0.2 μl for thalamic regions) over 10 min into each cannulae prior to the pentobarbitone injection. Brains were removed and frozen at −80°C; later coronal sections were cut at 20 μm. Each slice was photographed by a fixed digital camera to document the site and extent of the methylene blue dye diffusion, which was mapped (Paxinos & Watson 1986) using PHOTOSHOP (Adobe Systems Incorporated, San Jose, CA, U.S.A.) (Fig. 1). Rats in which the cannulae were incorrectly placed were excluded from the data analysis of the effects of the treatments.

image

Figure 1.   Coronal slice drawings (adapted from Paxinos & Watson, 1986) showing each animal’s cannula placements from bilateral methylene blue injections into brain regions. Numbers represent distance (mm) from bregma. (A) Motor cortex (M1). (B) Primary somatosensory cortex (S1), and secondary somatosensory cortex (S2). (C) Ventrobasal thalamus (VB). (D) Caudal nucleus reticular thalamus (nRT) injections.

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Data analysis

Statistical analysis was performed using GRAPHPAD PRISM version 4.00 for Windows; GraphPad Software, San Diego, CA, U.S.A., http://www.graphpad.com. Nonparametric statistics were used. The effect of treatment on the EEG end points of (1) total time in seizure, (2) number of seizures per minute, and (3) average seizure duration was compared between the treatment arms using the Friedman repeated measures analysis of variance (ANOVA). If a significant treatment effect was found, a post hoc Dunn’s multiple comparison test was performed to compare the effect of each of the NPY doses with that of saline. The instantaneous cycle frequency of the SWDs was compared between saline and the 1.5 mm NPY injections using the Wilcoxon matched pairs test. Significance was set at p < 0.05 (two-tailed) for all tests.

Results

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Site and extent of local diffusion from injection site

All animals that had a correct cannulae placement verified by methylene blue dye were included in the data set. Figure 1 illustrates the site and extent of local diffusion following methylene blue injection of each of the rats in each of the regions. In the motor cortex (Fig. 1A), diffusion is mostly located centrally and medially in the M1 area, but also spreads to the M2 area in the anterior section. All S1 injections remained within the target region with minimal diffusion into neighboring regions (Fig. 1B). Injections into the S2 region overlapped into the upper lip region of the primary somatosensory cortex (S1ULp) (Fig. 1B). Most dye injections aimed at the VB region were located in the ventral posteromedial thalamic nucleus (VPM) more than the ventral posterolateral thalamic nucleus (VPL), both of which combine to make the VB region, with some injections also diffusing into the posterior sections dorsal and medially into the posterior thalamic nuclear group (Po) and the laterodorsal thalamic nucleus, ventrolateral part (LDVL) (Fig. 1C). Overall dye injected into the nRT was well localized to this structure, with only a small spread into the dorsal region of the VB in anterior sections (Fig. 1D).

Focal NPY administration into the S2 region of the somatosensory cortex suppresses seizure expression in GAERS more potently than in S1 or motor cortex

Bilateral injection of NPY into either of the somatosensory regions (S1 and S2) resulted in a dose-dependent decrease of time in seizure over the 90-min posttreatment EEG recording compared to saline control injections (Fig. 2A). However, this effect was only significant for the S2 injections (Friedman’s ANOVA, F = 11.40, p = 0.004), with post hoc analysis showing a significant effect for the 1.5 nm NPY dose compared to control (7 ± 3% of saline, p < 0.01) in this region. The effect of the NPY injections into the S1 region did not attain statistical significance (F = 5.60, p = 0.13). There was also no significant effect of the NPY injections into the M1 region on percentage time in seizure compared to saline injections (F = 0.15, p = 0.99) (Fig. 2A).

image

Figure 2.   The effect on seizure expression following bilateral NPY injections into the cortex or thalamus in freely moving GAERS. All data expressed as a percentage of saline postinjection for the 90-min postinjection recording. (A) Time in seizure: M1 n = 8, S1 n = 6, S2 n = 6. (B) Number of seizures per minute: M1 n = 8, S1 n = 6, S2 n = 6. (C) Average seizure duration: M1 n = 8, S1 n = 5, S2 n = 4. (D) Time in seizure: nRT n = 6, VB n = 7. (E) Number of seizures per minute: nRT n = 6, VB n = 7. (F) Average seizure duration: nRT n = 6, VB n = 7. Friedman’s repeated measures ANOVA with post hoc Dunn’s multiple comparison test comparing the effect of each of the NPY doses with that of saline: *p ≤ 0.05, **p ≤ 0.01.

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The number of seizures per minute also showed a dose-dependent decrease for NPY injections into both somatosensory regions, but again this was only statistically significant for the S2 injections (F = 10.60, p = 0.007) but not the S1 injections (F = 2.60, p = 0.51, repeated measures ANOVA) (Fig. 2B). There was no decrease in the number of seizures per minute post NPY injections into the motor cortex (F = 0.72, p < 0.72).

Focal NPY injections had no effect on the average seizure duration at any of the cortical sites (Fig. 2C).

Focal NPY administration into the caudal nRT or VB does not significantly suppress seizures in GAERS

When NPY was administered bilaterally into the VB there was an increase in the average number of seizures per minute (F = 9.86, p = 0.02) (Fig. 2E) and a trend for an increased amount of time in seizures (F = 5.06, p = 0.17) (Fig. 2D), indicating that NPY had a seizure aggravating effect at this site. There was no significant effect on average seizure duration of the NPY microinjections into the VB region (F = 2.14, p = 0.54) (Fig. 2F). When bilateral NPY injections were made into the caudal nRT region there was no effect on total time in seizure (F = 1.80, p = 0.67) (Fig. 2D), or the average number of seizures per minute (F = 0.20, p = 0.99) (Fig. 2E). There was a small but significant decrease in the average seizure duration (F = 9.40, p = 0.02) when 0.5 mm NPY was injected into the nRT (Fig. 2F).

Focal administration of NPY into thalamocortical regions does not significantly affect the cycle frequency of the SWDs

There was no significant effect on the instantaneous cycle frequency of the SWDs of the 1.5 mm NPY injections versus saline injections into any of regions examined: S2: NPY 8.7 ± 0.7 Hz, saline 8.5 ± 0.5 Hz, p = 0.5; M1: NPY 7.9 ± 0.6 Hz, saline 8.2 ± 0.2 Hz, p = 0.3; VB: 8.5 ± 0.3 Hz, saline 8.0 ± 0.6, p = 0.06, nRT: NPY 8.2 ± 0.5 Hz, saline 8.3 ± 0.3 Hz, p = 0.1 (Fig. 3).

image

Figure 3.   Effect on instantaneous cycle frequency of the SWDs following bilateral NPY injections into brain regions (all 1.5 mm) compared with their respective control saline injections in GAERS (M1 n = 6, S2 n = 3, nRT n = 5, VB n = 5). *p ≤ 0.05, Wilcoxon matched pairs test.

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Discussion

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

This study investigated the sites within the thalamocortical circuitry in which NPY acts to suppress seizures in the GAERS model of absence epilepsy. The most marked antiseizure effect was seen when NPY was focally injected into the somatosensory cortex, with the amount of seizure suppression following injection into the S2 region significantly different to that following saline injections in the same region. No seizure suppression was seen following injections into the motor cortex or the thalamic regions. These findings indicate that the somatosensory cortex is most likely to be the primary site in the thalamocortical circuit in which NPY acts to suppress seizures in this animal model of absence epilepsy.

The thalamocortical circuit in humans and rodents is responsible for initiating and maintaining absence seizures (Danober et al., 1998). The circuit involves the nRT, the VB, and the cerebral cortex. The neural mechanisms underlying the generation of absence-related SWDs within the thalamocortical circuit have been widely debated for more than 50 years, with opposing views about whether the cortex, the thalamus, or both have primacy (Pinault & O’Brien, 2007). Over the last decade the “cortical focus” theory has become prominent (Meeren et al., 2002; Polack et al., 2007). Using multisite field recordings in awake and freely moving WAG/Rij rats (a phenotypically similar absence-epilepsy model to GAERS), Meeren et al. (2002) reported that seizures started in the perioral somatosensory region (S1) and then secondarily spread to other cortical and thalamic regions. Polack et al. (2007) performed intracellular electrographic recordings into the facial somatosensory cortex (S1) region of GAERS and reported that the neurons in the deep layers (V and VI) were more ictogenic in nature and also exhibited preictal oscillations compared to motor cortex and ventrobasal complex in the thalamus. Previous work by Pinault has shown that layer VI in the S1 cortex plays an important role in driving the propagation of SWDs (Pinault, 2003; Pinault et al., 2006). Recent work from our group studying oscillatory “seizure-like” network discharges in thalamocortical brain slices from GAERS cultured in vitro, demonstrated, using rapid calcium fluorescence imaging, that the discharges were initiated in the deep cortical layers before secondarily spreading to other cortical regions and the interconnected thalamus (Adams et al., 2011).

Neuropharmacologic studies have also supported the importance of the somatosensory cortical region in generating absence seizures in these rat models. Polack et al. (2009) demonstrated that injecting a sodium channel blocker (tetrodotoxin) focally into the S1 somatosensory cortex in GAERS blocked spontaneous seizures, whereas it did not produce the same effect when delivered to the motor cortex or thalamus. Other groups have also shown that focal injection drugs that suppress neuronal firing into the S1 somatosensory cortex suppresses seizures in either GAERS or WAG/Rij rats, including lidocaine (Sitnikova & van Luijtelaar, 2004) and ethosuximide (Richards et al., 2003; Manning et al., 2004; Gurbanova et al., 2006).

The results reported here provide further support for the importance of the somatosensory cortex in initiating these electroclinically “generalized” seizures in the GAERS model. The study provides several further novel observations. First, this is the first study to demonstrate that an endogenous anticonvulsant, namely NPY, acts primarily in the somatosensory cortex and not the thalamus to suppress seizures, although that it is important to note that pharmacologic rather than physiologic doses were used. Second, although the previous electrophysiologic and physiologic studies had concentrated on the S1 region of the somatosensory cortex, and the relationship of this compared to motor cortical and thalamic regions, this study also investigated the effects of focal NPY injections into the S2 cortical region. It is notable that seizure suppression following injection into S2 was found to be greater than following injection into S1, suggesting that this region may actually be more critical to seizure generation.

This study did not investigate the cellular mechanism of action of NPY to suppress seizures in the somatosensory cortex. Our previously published data using i.c.v. injections of specific Y-subtype agonists and antagonists, indicates that Y2 is the Y receptor subtype that has the strongest seizure-suppressing effects in GAERS, but activation of Y5 and Y1 receptors also suppressed seizures (Morris et al., 2007). However, Y2 receptors have been reported to be expressed at relatively low levels in rat somatosensory cortex compared with Y5 receptors (Parker & Herzog, 1999). It is possible that the pattern of expression of Y receptor subtypes is altered in GAERS, and examining this, along with focal injection of selective agonists for Y-receptor subtypes, is the focus of future work to define the cellular mechanisms mediating the effect of focal NPY injections into the S2 cortex.

In contrast to the effects seen with focal cortical administration, we found that focal injections of NPY into the VB paradoxically aggravated the number of seizures occurring in our GAERS rats, with a strong trend to have an increased total time in seizure postinjection (Fig. 2D,E). This is reminiscent of the effect we also found with focal injections of the AED carbamazepine into this structure in GAERS, which we showed was mediated by GABAA receptors (Liu et al., 2006). We proposed that this resulted in hyperpolarization of thalamocortical neurons within the VB, thereby de-inactivating low threshold calcium channels, making the cells more liable to fire in oscillatory bust firing mode and so promoting absence seizures. Consistent with this, others have shown that enhancing GABA activity locally in the VB thalamus by injection of the GABA transaminase inhibitor, γ-vinyl GABA, aggravates seizures in GAERS (Liu et al., 1991), and that microinjections of the GABAA agonist, muscimol, into the VB enhance spontaneous absence-like seizures in epileptic mice (Hosford et al., 1997). NPY actions at postsynaptic Y1 and Y5 receptors located on somata and dendrites of thalamocortical neurons in the VB enhance hyperpolarization of the VB thalamocortical neurons via activation of G-protein–activated inwardly rectifying potassium (GIRK) channels (Sun et al., 2001; El Bahh et al., 2005), which could therefore also explain the effects of focal NPY administration at this site to aggravate absence seizures in GAERS.

We did not demonstrate any effects on seizures of NPY injections into the caudal nRT. We chose to inject the caudal part of the nRT because this region receives direct inputs from the somatosensory cortex and projects to the ventrobasal thalamic relay nuclei that are primarily involved in SWDs (Vergnes et al., 1987; Pinault & Deschênes, 1998; Pinault, 2003). In contrast, the rostral nRT receives inputs primarily from motor and limbic structures, and projects to the anterior, intralaminar, and midline thalamic nuclei (Pinault & Deschênes, 1998; Aker et al., 2006), regions demonstrated on depth recordings not to be primarily involved in the SWDs (Vergnes et al., 1987). However it is likely that the rostral part of the nRT plays a role in modulating the propagation and maintenance of SWDs in genetic rat models, and a recent lesional study in the WAG/Rij rat suggested that this region may actually be more important for this than the caudal nRT (Aker et al., 2006; Meeren et al., 2009). Focal injections of the GABAA receptor antagonist, bicuculline, into either the rostral or caudal nRT has been shown to have effects that were opposite to those on SWDs in GAERS, with the former suppressing and the latter increasing SWD duration (Aker et al., 2006).

The findings of this study and other studies, indicate that genetically determined, phenotypically “generalized” seizures can be generated by relatively restricted regions of cerebral cortex is of clinical as well as scientific importance. This is reflected in the recently proposed Revised Terminology and Concepts for Organization of Seizures and Epilepsies of the International League Against Epilepsy (Berg et al., 2010) which, moving away from the traditional concept of these seizures being “generalized” from their onset, conceptualizes generalized seizures as “originating at some point within, and rapidly engaging, bilaterally distributed networks. Such bilateral networks can include cortical and subcortical structures, but do not necessarily include the entire cortex.” The clinical relevance is that this potentially opens up the prospect that focal drug delivery systems, administering NPY or other seizure suppressing compounds via mechanical, viral, or stem cell technology, could be applied to control seizures in patients with medically refractory genetic generalized epilepsies, not just those with focal epilepsies.

Acknowledgments

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

This work was supported by funding from the National Health and Medical Research Council of Australia (Project grants #568729 and #400106 to MJM and TO’B).

Disclosure

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

None of the authors has any conflict of interest 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.

References

  1. Top of page
  2. Summary
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
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