Excitation/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice.

CALFA G, LI W, RUTHERFORD M, POZZO-MILLER L

HIPPOCAMPUS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2015 p. 159 - 168

1050-9631

Rett syndrome (RTT) is a neurodevelopment disorderassociated with intellectual disabilities and caused by loss-of-functionmutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes incortical excitability occur in RTT individuals and Mecp2-deficient mice,including hippocampal network hyperactivity and higher frequency ofspontaneous multiunit spikes in the CA3 cell body layer. Here, wedescribe impaired synaptic inhibition and an excitation/inhibition (E/I)imbalance in area CA3 of acute slices from symptomatic Mecp2 knockoutmale mice (referred to as Mecp2-/y). The amplitude of TTX-resistantminiature inhibitory postsynaptic currents (mIPSC) was smaller in CA3pyramidal neurons of Mecp2-/y slices than in wildtype controls, whilethe amplitude of miniature excitatory postsynaptic currents (mEPSC)was significantly larger in Mecp2-/y neurons. Consistently, quantitativeconfocal immunohistochemistry revealed significantly lower intensity ofthe alpha-1 subunit of GABAARs in the CA3 cell body layer of Mecp2-/ymice, while GluA1 puncta intensities were significantly higher inthe CA3 dendritic layers of Mecp2-/y mice. In addition, the input/output(I/O) relationship of evoked IPSCs had a shallower slope in CA3 pyramidalneurons Mecp2-/y neurons. Consistent with the absence of neuronaldegeneration in RTT and MeCP2-based mouse models, the density ofparvalbumin- and somatostatin-expressing interneurons in area CA3 wasnot affected in Mecp2-/y mice. Furthermore, the intrinsic membraneproperties of several interneuron subtypes in area CA3 were notaffected by Mecp2 loss. However, mEPSCs are smaller and less frequentin CA3 fast-spiking basket cells of Mecp2-/y mice, suggesting animpaired glutamatergic drive in this interneuron population. Theseresults demonstrate that a loss-of-function mutation in Mecp2 causesimpaired E/I balance onto CA3 pyramidal neurons, leading to a hyperactivehippocampal network, likely contributing to limbic seizures inMecp2-/y mice and RTT individuals.