• Amygdala;
  • development;
  • fear;
  • hippocampus;
  • learning;
  • mef2;
  • memory;
  • review;
  • transcription;
  • viral vector


  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments

In the brain, transcription factors are critical for linking external stimuli to protein production, enabling neurons and neuronal networks to adapt to the ever-changing landscape. Gene transcription and protein synthesis are also vital for the formation of long-term memory. Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors have a well-characterized role in the development of a variety of tissues, but their role in the adult brain is only beginning to be understood. Recent evidence indicates that MEF2 regulates the structural and synaptic plasticity underlying memory formation. However, in stark contrast to most other transcription factors implicated in memory, MEF2-mediated transcription constrains (rather than promotes) memory formation. Here, we review recent data examining the role of MEF2 in adult memory formation in rodents.

Myocyte-enhancing factor 2 (MEF2) proteins are an evolutionarily conserved family of transcription factors that are present in organisms ranging from yeast and worms to mammals. Although first identified in muscle cells, the four different vertebrate Mef2 genes (Mef2A–D) are expressed in a wide range of tissues including both smooth and skeletal muscle, bone, lymphocytes and the brain (Potthoff & Olson 2007). MEF2 proteins are important both during development and adulthood, regulating transcriptional programs related to cell differentiation, proliferation, morphogenesis, survival and apoptosis (McKinsey et al. 2002; Potthoff & Olson 2007). In the adult brain, MEF2 proteins are widely, but differentially, expressed, suggesting that MEF2 proteins are involved in multiple processes and that the activity of MEF2 is highly regulated. Mounting evidence also indicates that MEF2 regulates activity-dependent synaptogenesis and long-term memory formation in the adult brain, adding MEF2 to a relatively short list of transcription factors that may mediate memory formation. However, the role of MEF2 in memory formation appears to be unique. Unlike classical transcriptions factors such as CREB, whose activity is thought to be necessary for memory formation (Josselyn & Nguyen 2005), MEF2 activity constrains memory formation. Interestingly, MEF2 as well as a number of MEF2 target genes have been implicated in a several neuropsychiatric and cognitive disorders, including autism-spectrum disorders and intellectual disability. These findings suggest that at least some of the cognitive deficits associated with these disorders may be attributable to dysregulation of MEF2 function.

Biology of MEF2

  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments

MEF2 structure and expression

Vertebrates have four different MEF2 proteins (MEF2A–D), all of which are composed of three functional domains: a highly conserved N-terminal MCM1-Agamous-Deficiens-Serum response factor (MADS) box domain, a conserved MEF2 domain and a highly divergent C-terminal transcriptional activation domain. The MADS box is primarily responsible for DNA binding to an A/T-rich domain in MEF2 target genes (Andres et al. 1995; Molkentin et al. 1996b), whereas the MEF2 domain regulates DNA-binding affinity and cofactor interactions (Black & Olson 1998; McKinsey et al. 2002) as well as heterodimerization and homodimerization with other MEF2 proteins (Molkentin et al. 1996a; Yu 1996). The C-terminal transcriptional activation domain differs among the MEF2 proteins and undergoes complex alternative splicing depending on the tissue (Martin et al. 1994; McDermott et al. 1993), resulting in wide functional diversity.

In both the developing and adult vertebrate brain, the four MEF2 proteins show distinct, but overlapping, expression patterns (Heidenreich & Linseman 2004; Ikeshima et al. 1995; Leifer et al. 1993, 1994; Lin et al. 1996; Lyons et al. 1995). MEF2 proteins are expressed throughout the adult brain, including regions involved in formation of different types of memory such as the cortex, hippocampus, amygdala and striatum. Expression of these MEF2 subtypes appears to be differentially regulated in a region- and cell-specific manner. For example, all four MEF2 subtypes are present in the dentate gyrus of the hippocampus, but only MEF2A, C and D are expressed in the thalamus and cerebellum (Lyons et al. 1995). Within the cerebellum, MEF2C mRNA appears to display strongest expression in Purkinje cells, whereas MEF2A and D mRNA are preferentially expressed in the granule cell layer. A summary of MEF2 expression in different brain regions involved in memory formation is shown in Table 1.

Table 1. Relative expression of MEF2 in brain regions involved in memory formation
  1. Data for expression of MEF2 mRNA and protein were compiled from Leifer et al. (1993, 1994), Lyons et al. (1995), Ikeshima et al. (1995), Lin et al. (1996) and Pulipparacharuvil et al. (2008). As protein expression generally mirrored mRNA expression, results from these studies were integrated in order to better illustrate the overlapping, yet differential expression of MEF2 subtypes in these adult brain regions (+, moderate expression; ++, intermediate expression; +++, strong expression; −, no expression detected).

Olfactory bulb++++++
Striatum (incl. nucleus accumbens)+++++
Purkinje cell layer+++
Granule cell layer+++++

Regulation of MEF2 activity

The regulation of MEF2 activity is complex. MEF2-dependent gene transcription depends not only on the nature of extracellular stimuli (McKinsey et al. 2002) but also on the complement of MEF2 isoforms expressed within a cell (including alternatively spliced variants), isoform dimerization, regulated degradation and phosphorylation state (Ornatsky & McDermott 1996; Yin et al. 2012). Indeed, phosphorylation and dephosphorylation of MEF2 regulate a large number of processes related to MEF2 function, including modulation of DNA-binding affinity, association with transcriptional co-regulators or co-repressors, acetylation and sumoylation, nuclear and cytoplasmic trafficking and caspase-mediated degradation (Heidenreich & Linseman 2004; Li et al. 2001; Shalizi et al. 2006; Yin et al. 2012) (Fig. 1).


Figure 1. Regulation of MEF2 expression and activity. Schematic illustrating some of the ways in which MEF2 can be regulated in neurons. In blue are modulatory elements that act on MEF2 to increase MEF2 activity, while modulations that decrease MEF2 activity are shown in red. Increased or decreased MEF2 activity can be manifested through alterations in DNA-binding affinity (PKA, CKII and GSK3β), transcriptional activity (p38, ERK5 and CaMKIV), shuttling to the nucleus (PP2B action on MEF2C), regulation of the acetylation (Ac) or sumoylation (Sm) of a specific C-terminal residue (PP2B and cdk5) in MEF2A/D, lysosomal degradation (HSc70 binding) and caspase-mediated degradation. In addition, HDAC binding, which represses MEF2 activity, can be promoted or inhibited by PP1α or CaMKIIα, respectively.

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There are eight reported phosphorylation sites in the transactivation domain of MEF2A, demonstrating the diverse regulation of MEF2 activity by various kinases and phosphatases (Shalizi & Bonni 2005). Phosphorylation in the transactivating domain by p38 MAP kinases (MEF2A and C) (Han et al. 1997; Wu et al. 2000a) or ERK5 (MEF2A, C and D) (Kato et al. 2000) increases the transcriptional activity of MEF2, whereas both GSKβ (MEF2D) and cdk5-mediated phosphorylation (MEF2A, C and D) reduce MEF2-dependent transcription (Gong et al. 2003; Wang et al. 2009). Notably, phosphorylation at Ser408/444 of MEF2A/D by cdk5 inhibits MEF2 transcriptional activity in HEK-293T cells (Pulipparacharuvil et al. 2008) and cultured neurons (Gong et al. 2003) and pMEF2 has been used as a marker for reduced MEF2 activity in the brain (discussed below). Also, cdk5 phosphorylation promotes sumoylation of MEF2 in vitro (Lys403/439, MEF2A/D) (Gregoire et al. 2006; Shalizi et al. 2006). Sumoylated MEF2A is a transcriptional repressor (Shalizi et al. 2006) and it has been suggested (Gregoire et al. 2006) that sumoylation may also increase the caspase-mediated degradation of MEF2A and D (but not MEF2C) (Tang et al. 2005). Outside of the transactivation domain, both casein kinase II and protein kinase A phosphorylation increase the DNA-binding affinity of MEF2 (Du et al. 2008; Molkentin et al. 1996b, Wang et al. 2005).

Calmodulin-dependent protein kinases (CaMK) also modulate MEF2 function, both directly and indirectly. While MEF2D appears to be directly phosphorylated in vitro by CaMKIV, resulting in increased transcriptional activity (Blaeser et al. 2000), there is an indirect role for a CaMK-mediated increase of MEF2 activity through modulation of HDACs. HDACs can bind to MEF2 and repress MEF2 activity. CaMK-mediated phosphorylation of HDACs (and possibly binding to HDACs directly) results in dissociation of HDACs from MEF2 (McKinsey et al. 2000a), allowing HDAC to be exported from the nucleus through interaction with 14-3-3 protein (Grozinger & Schreiber 2000; McKinsey et al. 2000b). The newly liberated MEF2 is then free to interact with transcriptional co-activators and promote MEF2-dependent gene transcription. Interestingly, CaMKI and CaMKIV have been implicated in MEF2 derepression in muscle cells (Kao et al. 2001; Lu et al. 2000), whereas in cultured neurons, evidence suggests the involvement of αCaMKII (Linseman et al. 2003), a kinase critical for synaptic plasticity and memory formation, in MEF2-dependent transcription. In addition to multiple phosphorylation sites, MEF2 may also be differentially regulated by phosphorylation state depending on the tissue- or cell-type. In T lymphocytes, p38-mediated phosphorylation of three residues, T293, T300 and T387, is necessary for MEF2C action (Han et al. 1997). However, phosphorylation of only T293 by p38 is required for MEF2C activation in differentiating myocytes (Wu et al. 2000b).

MEF2 activity is also regulated by several phosphatases. Protein phosphatase 2B (PP2B) or calcineurin is a calcium-dependent serine/threonine phosphatase implicated in some forms of synaptic depression (Wang & Kelly 1997) and which negatively regulates memory formation (Malleret et al. 2001; Mansuy et al. 1998). While calcineurin interacts with multiple transcription factors, one mechanism by which calcineurin may negatively regulate memory is via dephosphorylation of MEF2 (Ser408/444, MEF2A/D) (Flavell et al. 2006; Gregoire et al. 2006; Shalizi et al. 2006). Calcineurin can increase MEF2 binding to DNA and MEF2-dependent transcription (Cohen & Greenberg 2008; Greer & Greenberg 2008; Mao & Wiedmann 1999). Dephosphorylation of MEF2 by calcineurin also triggers a switch from sumoylation to acetylation of Lys403 in MEF2A (Shalizi et al. 2006). The increase in MEF2-dependent transcription reduces synapse number in cultured hippocampal neurons (Flavell et al. 2006) and inhibits dendritic morphogenesis in cultured cerebellar granule cells (Shalizi et al. 2006). Interestingly, MEF2C appears to be regulated by calcineurin in a distinct manner from MEF2A/D as calcineurin action on a residue specific to MEF2C (Ser412) results in increased nuclear accumulation (Lynch et al. 2005). Protein phosphatase 1α (PP1α), a phosphatase involved in long-term synaptic potentiation and memory formation, binds to MEF2 as well and recruits class II histone deacetylases (HDAC4 isoform) to MEF2 transcription complexes (Perry et al. 2009). In this way, PP1α can override calcineurin modulation and repress MEF2 activity.

In addition to phosphorylation, MEF2 function is regulated by decreasing levels of MEF2 protein itself. MEF2 proteins may be degraded by chaperone-mediated autophagy (CMA) (Yang et al. 2009). In a dopaminergic progenitor neuronal cell line, shuttling of MEF2D to the cytoplasm (which occurs under basal conditions) and subsequent interaction with the chaperone heat shock protein HSc70 promotes MEF2D lysosomal degradation. Inhibition of this CMA process results in accumulation of inactive MEF2D in the cytoplasm and increased cell death. Notably, a reduction of MEF2D-Hsc70 binding and increased cell death also occurs by increasing either wild-type α-synuclein or a mutated α-synuclein (A53T mutant) that is implicated in Parkinson's disease (PD)-associated neurodegeneration. Furthermore, increased levels of MEF2D in the brain are found in transgenic mouse model of PD (A53T α-synuclein mutant) as well as patients with PD (Yang et al. 2009). Therefore, the regulation of MEF2 activity is complex and depends on multiple factors.

Diversity of MEF2 signaling

The complexity of upstream signaling of MEF2 is mirrored by an equally complex downstream function; MEF2 stimulates the transcription of a wide array of genes. Flavell et al. (2008) used an elegant genome-wide targeting strategy and identified more than 180 activity-dependent MEF2 targets, including a large complement of genes important for synapse development and function. Interestingly, this screen detected genes thought to contribute to both synapse weakening (e.g. Homer 1a, kcna1 and kcna4 potassium channels) as well as synapse strengthening (e.g. bdnf and adenylyl cyclase 8). MEF2 targets also included genes that encode proteins involved in both excitatory and inhibitory synapses as well as neurotransmitter release. Collectively, this diverse array of genes that are involved in seemingly distinct neuronal processes suggest a sophisticated and multifaceted role for MEF2 that likely depends on factors such as age (development vs. adulthood), behavioral context (learning vs. basal conditions) as well as the MEF2 subtype involved. An example of this complexity comes from a study that showed differential regulation of BDNF expression depending on the MEF2 subtype involved. Specifically, a MEF2C splice variant lacking the γ-domain (which is particularly sensitive to membrane depolarization in rat cortical neurons in culture) was shown to selectively regulate increased expression of bdnf exon IV, whereas MEF2D limited depolarization-induced expression of bdnf exon I (Lyons et al. 2012).

Functional role of MEF2 in the adult brain

  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments

Research into the function of MEF2 in the brain initially focused on the role of this transcription factor in development. Interestingly, the temporal expression pattern of MEF2 isoforms correlates with the vertebrate developmental stages of neuronal differentiation, maintenance and survival (see Heidenreich & Linseman 2004 for review). Functional studies in vitro using cultured neurons have supported this role for MEF2 and have shed light onto the underlying mechanisms, including regulation of expression of growth factors (BDNF, Lyons et al. 2012), transcription factors that regulate synapse strength and number (c-Jun, Speksnijder et al. 2012) and miRNAs involved in dendritogenesis (miR-134, Fiore et al. 2009). More recently, the potential role of MEF2 in the adult brain has also been studied. The developmental studies on the role of MEF2 have greatly informed the studies examining the role of MEF2 in the adult brain, specifically with regard to the ability of MEF2 to regulate synapse formation and synaptic turnover, events critical for brain development, but which are also thought to be associated with memory formation in the adult.

Effect of MEF2 on dendritic spines

Perhaps, the first hint that MEF2 may be important for memory came from the observation that MEF2-mediated transcription disrupted dendritic spine growth in vitro (Flavell et al. 2006; Tian et al. 2010; Shalizi et al. 2006). Increasing MEF2 function decreased the number of dendritic spines and excitatory synapses in hippocampal neurons in vitro (Flavell et al. 2006) as well as inhibited the formation of dendritic claws (sites of excitatory input) in cultured cerebellar granule cells (Shalizi et al. 2006). As an increase in the synaptic strength between neurons is thought to underlie memory formation (Bailey & Kandel 1993; Bailey et al. 1996) and the majority of excitatory synapses occur on dendritic spines (Harris & Stevens 1988, 1989), it has long been thought that dendritic spines serve as storage sites for synaptic strength, an idea first proposed by Santiago Ramón y Cajal over 100 years ago (Cajal 1893). In this way, the growth and restructuring of dendritic spines is thought to be crucial for memory formation. Consistent with this notion, several human cognitive disorders are characterized by abnormal dendritic spine density and morphology (Nimchinsky et al. 2002). The finding, therefore, that MEF2-dependent transcription decreased dendritic spine growth (and that spine growth is required for memory formation) suggested that this transcription factor may also inhibit memory formation.

MEF2 and memory

The observations that MEF2 decreases spine growth and spine growth is thought to be important for memory formation lead to the prediction that memories are successfully formed only when endogenous MEF2 function is decreased. Experimental evidence from several types of studies indicates that during learning and successful memory formation MEF2 expression and activity is downregulated. Both the formation of spatial and fear memories and chronic cocaine treatment in mice are associated with a local increase in MEF2 phosphorylation (Ser408/444, MEF2A/D), a phosphorylation event associated with decreased MEF2-mediated transcription (Cohen & Greenberg 2008; Greer & Greenberg 2008) and a decrease in overall levels of MEF2 protein (Cole et al. 2012; Pulipparacharuvil et al. 2008). These data suggest that MEF2 protein is degraded during memory formation and is consistent with the emerging idea that protein degradation, along with protein synthesis, is an important component of synaptic plasticity and memory formation (Fioravante & Byrne 2011).

These findings indicate that memory formation is accompanied by a decrease in endogenous MEF2 levels and function. On the other hand, acutely increasing MEF2 activity in glutamatergic neurons of the hippocampus, amygdala (Cole et al. 2012) and anterior cingulate cortex (Vetere et al. 2011) disrupts memory formation perhaps by interfering with the spine growth that normally underlies memory formation. For example, Cole et al. (2012) observed that acute expression of a constitutively active form of MEF2 in the hippocampus impaired spatial memory formation (as measured by the ability to remember the location of a hidden platform during a Morris water maze task) and also prevented the learning-associated spine growth in hippocampal neurons normally observed with spatial memory formation. Similarly, expression of a constitutively active form of MEF2 in the amygdala impaired the formation of a conditioned fear memory. Conversely, knockdown of MEF2 (using a dominant-negative MEF2 or shRNAi directed against MEF2) in the hippocampus or amygdala enabled the formation of spatial or fear memory, respectively, under subthreshold learning conditions (i.e. conditions that are not normally sufficient to promote memory formation).

In addition to its effects on initial memory formation, MEF2 also plays a role in time-dependent reorganization and consolidation of a context memory. Hippocampal-dependent memories are thought to gradually reorganize over time; such initially hippocampal-dependent memories become less dependent on the hippocampus and more cortically mediated over time (Frankland & Bontempi 2005; Zola-Morgan & Squire 1990). Importantly, the anterior cingulate cortex is proposed to be a critical region mediating this shift (Frankland et al. 2004). Vetere et al. (2011) showed that inhibition of spine growth specifically in the anterior cingulate cortex by expression of a constitutively active form of MEF2 after a contextual fear conditioning task prevented consolidation of the fear memory.

The role of MEF2 in a drug of abuse type of ‘memory’ (behavioral sensitization to cocaine) in the nucleus accumbens (NAcc) has also been examined. As expected, acutely increasing MEF2 in the NAcc decreased spine density in GABA-ergic medium spiny neurons. Increasing MEF2 function also promoted both the acquisition and maintenance of cocaine-mediated locomotor sensitization and cocaine-mediated reward sensitization in mice (Pulipparacharuvil et al. 2008). These data highlight the different behavioral effects of MEF2 depending on the brain region and/or cell type.

Together, these findings in adult rodents are particularly interesting in light of a novel role proposed for MEF2 in metaplasticity during development. It has long been known that the history of a neuron impacts its future plasticity (Abraham & Bear 1996). In this way, neurons have a ‘memory’ of previous activity. To investigate the molecular mechanisms underlying metaplasticity, Haas and coworkers (Chen et al. 2012) used an elegant system that allowed them to visualize and measure structural (changes in dendritic processes) and functional (changes in calcium influx) plasticity in three dimensions in a developing brain over several hours. Using Xenopus tadpoles, they found that neuronal activity produced by an unpatterned visual stimulus (white noise, WN) that itself was not sufficient to produce structural or functional plasticity, nevertheless reduced the threshold for plasticity triggered by subsequent patterned stimuli. The time window for the reduced plasticity threshold (hours) correlated with transiently reduced MEF2 function. Interestingly, they observed that the decrease in MEF2 function was not associated with phosphorylation of MEF2, but rather caspase degradation of MEF2. Remarkably, decreasing MEF2A/D levels on its own (without WN stimulation) was sufficient to cause the metaplasticity effects. This finding is remarkably similar to the results in mice in which decreasing MEF2 function was sufficient to allow memory formation following subthreshold training. These results clearly show that decreasing MEF2 function mediates experience-dependent metaplasticity in the developing brain and a similar process in the adult brain.

It should be noted that the role of MEF2 in memory formation is not entirely consistent across all types of studies. For instance, transgenic mice chronically lacking various MEF2 subtypes in the brain show different spine density and behavioral phenotypes. Mice with brain-specific deletions of MEF2A or MEF2A/D showed no deficits in memory formation for a contextual fear conditioning task and no discernible changes in hippocampal spine density (Akhtar et al. 2012), whereas mice with brain-specific deletions of MEF2C showed deficits in contextual, but not cued, fear memory formation along with decreased spine density and synaptic transmission in the dentate gyrus (Barbosa et al. 2008). The different phenotypes produced by chronic and acute MEF2 manipulations may be attributed to the critical importance of MEF2 in neuronal development (Li et al. 2008; Potthoff & Olson 2007; Shalizi & Bonni 2005).

Mechanisms of MEF2 action

While MEF2 is known to influence a myriad of genes in the brain (Flavell et al. 2008), one of the MEF2 target genes critical for the memory-impairing effects of MEF2 may be arc (Activity-Regulated Cytoskeletal protein). Several studies show that MEF2 regulates Arc protein expression in vitro (Flavell et al. 2006) and in vivo (Cole et al. 2012). Arc decreases the surface expression of the AMPA-type glutamate receptors (AMPAR) by enhancing their endocytosis (Chowdhury et al. 2006), leading to decreased synaptic efficacy and the weakening of synapses similar to long-term depression or homeostatic synaptic scaling (Gainey et al. 2009; Malinow & Malenka 2002). Cole et al. (2012) found that in mice that have acutely increased MEF2 in the amygdala, concomitant disruption of AMPAR-regulated endocytosis (using an inhibitory peptide) rescued the MEF2-induced impairment in fear memory formation. On the basis of these results, the authors proposed that MEF2 normally disrupts memory formation by increasing Arc expression which then decreases surface expression of AMPARs, leading to synapse destabilization and elimination.

Huber and coworkers (2012) have presented a different mechanism for MEF2-mediated regulation of synapse density, but which still may be related to regulation of surface expression of AMPARs (Tsai et al. 2012). They showed that MEF2 activation in hippocampal neurons led to increased production of protocadherin 10 (Pcdh10), which is involved in ubiquitination and lysosomal targeting of the synaptic scaffold protein PSD-95. Attenuating Pcdh10-mediated degradation of PSD-95 in hippocampal neurons resulted in inhibition of both MEF2-mediated degradation of PSD-95 and MEF2-mediated synapse elimination. PSD-95 anchors AMPARs as well as other proteins at the synapse and decreasing functional synaptic PSD-95 can result in diffusion of synaptic AMPARs out of the synaptic cleft as well as AMPAR endocytosis (Bats et al. 2007; Colledge et al. 2003). Therefore, it is likely that MEF2 regulates surface expression of AMPARs and synapse stability through multiple mechanisms.

MEF2 in disease

  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments

The importance of MEF2 in the regulation and development of neural circuits in humans is highlighted by the fact that mutations of MEF2 as well as MEF2 target genes have been implicated in diseases such as epilepsy, autism and intellectual disability (Flavell et al. 2008; Le Meur et al. 2010; Morrow et al. 2008). Haploinsufficiency of MEF2C is linked to a severe form of intellectual disability (Le Meur et al. 2010) and mutations in a number of MEF2-regulated genes resulting in an improper balance of synaptic excitation and inhibition have been shown to lead to epilepsy (Kalachikov et al. 2002; Spauschus et al. 1999). Angelman syndrome, a disorder characterized by mental retardation and susceptibility to seizures, is caused by mutations in the MEF2-regulated gene ube3a (Dan & Boyd 2003; Greer et al. 2010).

Symptoms of epilepsy, Angelman syndrome and autism typically manifest early in the life of an individual, at a time when synapses are being developed and pruned in a sensory experience-dependent manner (Flavell et al. 2008). The ability of MEF2 to regulate spine formation in an activity-dependent manner suggests that there is a common mechanism underlying these disorders. Indeed, normal spine development is vital for cognition and memory formation (Greer et al. 2009) and forms of intellectual disability have been strongly linked to altered spine densities in both animal models (Nimchinsky et al. 2001) and human patients (Fiala et al. 2002). For instance, Fragile X syndrome (FXS), which is the most common form of inherited intellectual disability in boys and is associated with autism-like features (Bassell & Warren 2008), is characterized by increased spine density (Irwin et al. 2001, 2002), suggesting that a deficit in mechanisms that normally eliminate spines (Pfeiffer et al. 2010). Interestingly, Huber and coworkers (2010) found that increasing or decreasing MEF2 function had no effect on spine density in mice that model FXS (Pfeiffer et al. 2010), suggesting that MEF2 may act upstream of FMRP (Fragile X Mental Retardation Protein), the protein implicated in FXS. Furthermore, they showed that MEF2-mediated degradation of PSD-95 and MEF2-mediated synapse elimination are prevented in FMRP-lacking neurons owing to sequestration of proteins involved in ubiquitination and degradation of PSD-95 (Tsai et al. 2012). Therefore, further characterizing the MEF2 transcription program may provide key insights into the molecular causes of neurological/developmental diseases and may also provide potential targets for treatments of these disorders.

Concluding remarks—memory: a role for MEF2

  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments

The establishment of a link between MEF2-mediated transcription and regulation of memory formation has opened up an important avenue of research into a relatively unexplored mechanism that underlies memory formation and cognition. The molecular diversity of MEF2 isoforms and their gene products, along with the ability of MEF2 to either limit or enhance memory formation depending on cell type of brain region involved, suggests a complex, multifaceted and important role for this family of transcription factors in the developed brain. The key questions to be addressed in the immediate future include: under what circumstances would MEF2 either repress or enhance memory and what are the differential underlying mechanisms? Is this related to MEF2 isoform involved and/or the cell type expressing the relevant MEF2? What are the distinctions between MEF2 and other transcription factors such as CREB, particularly in cases in which MEF2 plays a facilitative role in memory formation? Given the links between MEF2 signaling and several CNS disorders, further understanding of the biology of MEF2 will not only increase our understanding of transcriptional control of memory formation but also allow greater insight into developing treatments for these conditions.


  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments
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  1. Top of page
  2. Abstract
  3. Biology of MEF2
  4. Functional role of MEF2 in the adult brain
  5. MEF2 in disease
  6. Concluding remarks—memory: a role for MEF2
  7. References
  8. Acknowledgments

This work was generously supported by the Canadian Institutes for Health Research (CIHR) and the National Sciences and Engineering Research Council of Canada (NSERC). The authors have no conflict of interest to declare.