title: Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission.
abstract: An imbalance between the strengths of excitatory and inhibitory synaptic inputs has been proposed as the cellular basis of autism and related neurodevelopmental disorders. Previous studies examining spontaneous levels of excitatory and inhibitory neurotransmission in the forebrain regions of methyl-CpG-binding protein 2 (Mecp2) mutant mice, models of the autism spectrum disorder Rett syndrome, have identified a decrease in excitatory drive, in some cases coupled with an increase in inhibitory synaptic strength, as a major source of this imbalance. Here, we reevaluated this question by examining the short-term dynamics of evoked neurotransmission between hippocampal neurons cultured from MeCP2 knockout mice and found a marked increase in evoked excitatory neurotransmission that is consistent with an increase in presynaptic release probability. This increase in evoked excitatory drive was not matched with alterations in evoked inhibitory neurotransmission. Moreover, we observed similar excitatory drive specific changes after the loss of key histone deacetylases (histone deacetylase 1 and 2) that form a complex with MeCP2 and mediate transcriptional regulation. These findings suggest a distinct role for MeCP2 and its cofactors in the regulation of evoked excitatory neurotransmission compared with their essential role in basal synaptic activity.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
authors.forename: Erika D
authors.initials: ED
authors.lastname: Nelson
authors.forename: Manjot
authors.initials: M
authors.lastname: Bal
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Monteggia
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2