Electrophysiological Phenotypes of Me CP 2 A140V Mutant Mouse Model

Summary Aims Me CP 2 gene mutations are associated with Rett syndrome and X‐linked mental retardation ( XLMR ), diseases characterized by abnormal brain development and function. Recently, we created a novel Me CP 2 A140V mutation mouse model that exhibited abnormalities of cell packing density and dendritic branching consistent with that seen in Rett syndrome patients as well as other Me CP 2 mutant mouse models. Therefore, we hypothesized that some deficits of neuronal and synaptic functions might also be present in the A140V mutant model. Methods Here, we tested our hypothesis in hippocampal slices using electrophysiological recordings. Results We found that in young A140V mutant mice (3‐ to 4‐week‐old), hippocampal CA 1 pyramidal neurons exhibited more positive resting membrane potential, increased action potential ( AP ) firing frequency induced by injection of depolarizing current, wider AP duration, and smaller after hyperpolarization potential compared to neurons prepared from age‐matched wild‐type mice, suggesting a neuronal hyperexcitation. At the synaptic level, A140V mutant neurons exhibited a reduced frequency of spontaneous IPSC s (inhibitory postsynaptic potentials) and an enhanced probability of evoked glutamate release, both suggesting neuronal hyperexcitation. However, hippocampal CA 1 long‐term potentiation was not significantly different between A140V and WT mice. In adult mice (11‐ to 13‐month‐old), in addition to neuronal hyperexcitation, we also found significant deficits of both short‐term and long‐term potentiation of CA 3‐ CA 1 synapses in A140V mice compared to WT mice. Conclusions These results clearly illustrate the age‐dependent abnormalities of neuronal and synaptic function in the Me CP 2 A140V mutant mouse model, which provides new insights into the understanding of the pathogenesis of Rett syndrome.