RESUMO
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.
Assuntos
Histona Desacetilases/metabolismo , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Proteínas de Arabidopsis/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Células Cultivadas , Condicionamento Psicológico/fisiologia , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/genética , Medo/fisiologia , Antagonistas GABAérgicos/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Histona Desacetilases/deficiência , Histona Desacetilases/genética , Humanos , Técnicas In Vitro , Transferases Intramoleculares/metabolismo , Deficiências da Aprendizagem/genética , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Teste de Desempenho do Rota-Rod , Bloqueadores dos Canais de Sódio/farmacologia , Sinapses/genética , Tetrodotoxina/farmacologia , TransfecçãoRESUMO
MEF2 (A-D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function.