tetrodotoxin and Learning-Disabilities

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.

Topics: Animals; Arabidopsis Proteins; CA1 Region, Hippocampal; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cells, Cultured; Conditioning, Psychological; Electric Stimulation; Excitatory Postsynaptic Potentials; Fear; GABA Antagonists; Green Fluorescent Proteins; Histone Deacetylases; Humans; In Vitro Techniques; Intramolecular Transferases; Learning Disabilities; Long-Term Potentiation; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Neurons; Patch-Clamp Techniques; Picrotoxin; Rotarod Performance Test; Sodium Channel Blockers; Synapses; Tetrodotoxin; Transfection

Lack of expression of the fragile X mental retardation protein (FMRP), due to silencing of the FMR1 gene, causes the Fragile X syndrome. Although FMRP was characterized previously to be an RNA binding protein, little is known about its function or the mechanisms underlying the Fragile X syndrome. Here we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit, GluR1, was decreased in the cortical synapses, but not in the hippocampus or cerebellum, of FMR1 gene knockout mice. Reduced long-term potentiation (LTP) was also found in the cortex but not in the hippocampus. Another RNA binding protein, FXR; the N-methyl-D-aspartate receptor subunit, NR2; and other learning-related proteins including c-fos, synapsin, myelin proteolipid protein, and cAMP response element binding protein were not different between FMR1 gene knockout and wild-type mice. These findings suggest that the depressed cortical GluR1 expression and LTP associated with FMRP deficiency could contribute to the Fragile X phenotype.

Topics: Animals; Cerebral Cortex; Cyclic AMP Response Element-Binding Protein; Down-Regulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression Regulation; Learning Disabilities; Liver; Long-Term Potentiation; Male; Mice; Mice, Knockout; Myelin Proteolipid Protein; Myocardium; Nerve Tissue Proteins; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA-Binding Proteins; Synapses; Synapsins; Synaptic Membranes; Synaptic Transmission; Tetrodotoxin