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

• Autores: Calfa, Gaston Diego; Li, Wei; Rutherford, John M.; Pozzo Miller, Lucas
• Año de publicación: 2015
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: E/I BALANCE; HIPPOCAMPUS; INTELLECTUAL DISABILITY; MECP2; RETT SYNDROME
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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 GABAARs 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.
Fil: Calfa, Gaston Diego. University of Alabama at Birmingahm; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina
Fil: Li, Wei. University of Alabama at Birmingahm; Estados Unidos
Fil: Rutherford, John M.. University of Alabama at Birmingahm; Estados Unidos
Fil: Pozzo Miller, Lucas. University of Alabama at Birmingahm; Estados Unidos