Excitation/inhibition imbalance due to desinhibition of CA3 pyramidal neurons causes network hyperexcitability in hippocampal slices from Mecp2 mutant mice: implications for seizure disorders in Rett syndrome

CALFA G, MD AMARAL, POZZO-MILLER L

Leesburg, Virginia

Congreso; 12th Annual Rett Syndrome Symposium, International Rett Syndrome Foundation (IRSF); 2011

IRSF

Rett syndrome (RTT) is a neurodevelopment disorder predominantly occurring in females caused by loss-of-function mutations in the transcriptional regulator MeCP2. Neuronal dysfunction and changes in cortical excitability were described in RTT individuals and Mecp2 deficient mouse models. We previously demonstrated network hyperexcitability in hippocampal slices from symptomatic Mecp2 mutant mice, where multiunit extracellular recordings from the CA3 cell body layer showed a higher frequency of spontaneous spikes (Calfa et al. 2011). We hypothesized that an excitation/inhibition (E/I) imbalance favoring excitation onto CA3 pyramidal cells is responsible of network hyperexcitability. To test this hypothesis, we performed whole-cell recordings from CA3 pyramidal neurons in acute slices from symptomatic Mecp2 mutant mice and age-matched wildtype littermates. The amplitude of spontaneous TTX-resistant miniature excitatory postsynaptic currents (mEPSC) was significantly larger in Mecp2 mutant neurons than in wildtype littermates, while the amplitude of miniature inhibitory postsynaptic currents (mIPSC) was smaller in the mutant slices. On the other hand, mEPSC frequency was lower in Mecp2 mutant neurons, and mIPSC frequency was higher in mutant neurons, suggesting a homeostatic compensation to increased excitatory input. Regarding action potential-dependent synaptic transmission, the input/output (I/O)
relationship of mossy fiber-evoked EPSCs had a higher slope in Mecp2 mutant CA3 pyramidal neurons, while the I/O curve of evoked IPSCs had a lower slope in Mecp2 mutant neurons. Taken together, these results demonstrate that a loss-of-function mutation in Mecp2 cause both impaired GABAergic input and enhanced glutamatergic input to CA3 pyramidal neurons, leading to an hyperexcitable hippocampal network, likely contributing to limbic seizures in Mecp2mutant mice and RTT individuals. We are currently testing whether Mecp2 dysfunction results in impaired development of GABAergic neurons and/or synapses within area CA3.