Learning and memory depend on the activity-dependent structural plasticity of synapses and changes in neuronal gene expression. We show that deletion of the MEF2C transcription factor in the CNS of mice impairs hippocampal-dependent learning and memory. Unexpectedly, these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission. Conversely, neuronal expression of a superactivating form of MEF2C results in a reduction of excitatory postsynaptic sites without affecting learning and memory performance. We conclude that MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampaldependent learning and memory.synaptic transmission ͉ synaptogenesis ͉ learning deficits N eurons process and retain information by forming synaptic connections that are modified by the intensity and frequency of their activity. The capacity to regulate the efficacy of synaptic transmission is essential for the continual remodeling of neural networks required for cognitive processes such as learning and memory. Distinct molecular mechanisms control synaptic plasticity associated with the different temporal stages of memory. A short-term process lasting minutes depends on modifications of preexisting proteins, whereas a long-term process lasting hours and days depends on changes in gene expression and protein synthesis (1).Originally identified as regulators of muscle development, members of the MEF2 (Myocyte Enhancer Factor 2) family of MADS (MCM1, agamous, deficiens, serum response factor) box transcription factors are expressed in overlapping but distinct regions of the CNS that correlate with the withdrawal of neurons from the cell cycle and acquisition of a differentiated phenotype (2). Mef2c is the first of four Mef2 genes to be expressed in the CNS and, in the adult brain, is highly expressed in the frontal cortex, entorhinal cortex, dentate gyrus, and amygdala (3, 4). RNA interference-mediated knockdown of MEF2A and MEF2D in cultured hippocampal neurons increases the number of excitatory synapses and the frequency of miniature excitatory postsynaptic currents (mEPSCs) (5). These alterations depend on the ability of the MEF2 proteins to stimulate neural activitydependent transcription of target genes (5). In contrast, loss of MEF2A in cerebellar granule neurons results in a decrease in the number of dendritic claws (6).Here, we present an analysis of the neuronal functions of the Mef2 gene in vivo. Through conditional deletion of Mef2c and expression of a superactive form of MEF2C in neurons of mice, we show that this MEF2 isoform plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. ResultsBrain-Specific Deletion of MEF2C. We deleted Mef2c specifically in the CNS by breeding Mef2c loxP/loxP females (7) to Mef2c KO/ϩ heterozygous male (8) mice h...

DNA methylation is an epigenetic mechanism that plays a critical role in the repression of gene expression. Here, we show that DNA methyltransferase (DNMT) inhibition in hippocampal neurons results in activity-dependent demethylation of genomic DNA and a parallel decrease in the frequency of miniature EPSCs (mEPSCs), which in turn impacts neuronal excitability and network activity. Treatment with DNMT inhibitors reveals an activity-driven demethylation of brain-derived neurotrophic factor promoter I, which is mediated by synaptic activation of NMDA receptors, because it is susceptible to AP-5, a blocker of NMDA receptors. The specific effect of DNMT inhibition on spontaneous excitatory neurotransmission requires gene transcription and is occluded in the absence of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Interestingly, enhancing excitatory activity, in the absence of DNMT inhibitors, also produces similar decreases in DNA methylation and mEPSC frequency, suggesting a role for DNA methylation in the control of homeostatic synaptic plasticity. Furthermore, adding excess substrate for DNA methylation (S-adenosyl-L-methionine) rescues the suppression of mEPSCs by DNMT inhibitors in wild-type neurons, as well as the defect seen in MeCP2-deficient neurons. These results uncover a means by which NMDA receptor-mediated synaptic activity drives DNA demethylation within mature neurons and suppresses basal synaptic function.

Mutations in the transcriptional repressor, methyl-CpG binding protein 2 (MeCP2), result in a neurodevelopmental disorder called Rett Syndrome (RTT) . Based on the neurological phenotypes observed in Rett patients, we examined the potential role of MeCP2 in synaptic function. We compared elementary properties of synaptic transmission between cultured hippocampal neurons from MeCP2 knockout and wild-type littermate control mice and found a decrease in the frequency of spontaneous excitatory synaptic transmission (mEPSCs) in neurons lacking MeCP2. We also detected a significant increase in the rate of short-term synaptic depression. To explore whether these functional effects can be attributed to MeCP2's role as a transcriptional silencer, we treated cultures with a drug that impairs histone deacetylation and examined spontaneous synaptic transmission. Treatment with this compound induced a similar decrease in mEPSC frequency in wild-type control cultures, but this decrease was occluded in MeCP2-deficient neurons. Interestingly, neither the loss of MeCP2 nor the drug treatment resulted in changes in mIPSC properties. Finally, by means of a lentivirus expressing Cre recombinase, we show that loss of MeCP2 function after neurodevelopment and synaptogenesis was sufficient to mimic the decrease in mEPSC frequency seen in constitutive MeCP2 KO neurons. Taken together, these results suggest a role for MeCP2 in control of excitatory presynaptic function through regulation of gene expression.

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BackgroundA large body of literature suggests that certain polysaccharides affect immune system function. Much of this literature, however, consists of in vitro studies or studies in which polysaccharides were injected. Their immunologic effects following oral administration is less clear. The purpose of this systematic review was to consolidate and evaluate the available data regarding the specific immunologic effects of dietary polysaccharides.MethodsStudies were identified by conducting PubMed and Google Scholar electronic searches and through reviews of polysaccharide article bibliographies. Only articles published in English were included in this review. Two researchers reviewed data on study design, control, sample size, results, and nature of outcome measures. Subsequent searches were conducted to gather information about polysaccharide safety, structure and composition, and disposition.ResultsWe found 62 publications reporting statistically significant effects of orally ingested glucans, pectins, heteroglycans, glucomannans, fucoidans, galactomannans, arabinogalactans and mixed polysaccharide products in rodents. Fifteen controlled human studies reported that oral glucans, arabinogalactans, heteroglycans, and fucoidans exerted significant effects. Although some studies investigated anti-inflammatory effects, most studies investigated the ability of oral polysaccharides to stimulate the immune system. These studies, as well as safety and toxicity studies, suggest that these polysaccharide products appear to be largely well-tolerated.ConclusionsTaken as a whole, the oral polysaccharide literature is highly heterogenous and is not sufficient to support broad product structure/function generalizations. Numerous dietary polysaccharides, particularly glucans, appear to elicit diverse immunomodulatory effects in numerous animal tissues, including the blood, GI tract and spleen. Glucan extracts from the Trametes versicolor mushroom improved survival and immune function in human RCTs of cancer patients; glucans, arabinogalactans and fucoidans elicited immunomodulatory effects in controlled studies of healthy adults and patients with canker sores and seasonal allergies. This review provides a foundation that can serve to guide future research on immune modulation by well-characterized polysaccharide compounds.