title: Excitation/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice.
abstract: Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multiunit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inhibition and an excitation/inhibition (E/I) imbalance in area CA3 of acute slices from symptomatic Mecp2 knockout male mice (referred to as Mecp2(-/y) ). The amplitude of TTX-resistant miniature inhibitory postsynaptic currents (mIPSC) was smaller in CA3 pyramidal neurons of Mecp2(-/y) slices than in wildtype controls, while the amplitude of miniature excitatory postsynaptic currents (mEPSC) was significantly larger in Mecp2(-/y) neurons. Consistently, quantitative confocal immunohistochemistry revealed significantly lower intensity of the alpha-1 subunit of GABAA Rs in the CA3 cell body layer of Mecp2(-/y) mice, while GluA1 puncta intensities were significantly higher in the CA3 dendritic layers of Mecp2(-/y) mice. In addition, the input/output (I/O) relationship of evoked IPSCs had a shallower slope in CA3 pyramidal neurons Mecp2(-/y) neurons. Consistent with the absence of neuronal degeneration in RTT and MeCP2-based mouse models, the density of parvalbumin- and somatostatin-expressing interneurons in area CA3 was not affected in Mecp2(-/y) mice. Furthermore, the intrinsic membrane properties of several interneuron subtypes in area CA3 were not affected by Mecp2 loss. However, mEPSCs are smaller and less frequent in CA3 fast-spiking basket cells of Mecp2(-/y) mice, suggesting an impaired glutamatergic drive in this interneuron population. These results demonstrate that a loss-of-function mutation in Mecp2 causes impaired E/I balance onto CA3 pyramidal neurons, leading to a hyperactive hippocampal network, likely contributing to limbic seizures in Mecp2(-/y) mice and RTT individuals.
authors.affiliation: Department of Neurobiology, Civitan International Research Center, The University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Gaston
authors.initials: G
authors.lastname: Calfa
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: John M
authors.initials: JM
authors.lastname: Rutherford
authors.forename: Lucas
authors.initials: L
authors.lastname: Pozzo-Miller
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000503:physiopathology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000502:physiology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D055369:Miniature Postsynaptic Potentials; D009433:Neural Inhibition / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000503:physiopathology*; D018091:Receptors, AMPA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D015518:Rett Syndrome; D013569:Synapses / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; C546241:Gabra1 protein, mouse; C497393:Mecp2 protein, mouse
keywords: E/I balance; Hippocampus; MeCP2; Rett syndrome; intellectual disability