Excitation/inhibition imbalance and hippocampal network hyperexcitability in Mecp2 mutant mice: A role of impaired BDNF-TRPC channel signaling in CA3 interneurons

W. LI, G. CALFA, L. POZZO-MILLER

Congreso; Society for Neuroscience International Congress; 2012

Proper function of the hippocampal network requires a balance between excitatory (E) and inhibitory (I) input onto pyramidal neurons, more so for CA3 neurons, which are highly interconnected by excitatory recurrent collaterals. In addition to cognitive and learning & memory impairments, such E/I imbalance contributes to seizures disorders, which are common in Rett syndrome. Indeed, the hippocampal network is hyperexcitable in symptomatic Mecp2 mutant mice (Calfa et al. J Neurophysiol, 2011). We found that the amplitude of miniature inhibitory postsynaptic currents (mIPSC) and the slope of the input/output relationship of evoked IPSCs were smaller in Mecp2 mutant CA3 pyramidal neurons than those in wildtype neurons. The intrinsic properties of CA3 GABAergic interneurons, including current-spiking relationships, were unaffected in Mecp2 mutant slices. The amplitude of mEPSCs and mIPSCs, as well as of evoked EPSCs and IPSCs recorded in CA3 interneurons are comparable in Mecp2 mutant mice and wildtype controls. Altogether, these observations suggest that the E/I imbalance in Mecp2 mutant CA3 pyramidal neurons originates from impaired GABA release at the level of presynaptic terminals rather than from reduced interneuron excitability or weak excitatory inputs onto CA3 interneurons. Maturation of presynaptic transmitter release from GABAergic interneurons is highly dependent on BDNF levels, which are lower in several brain regions of Mecp2 mutant mice, including the hippocampus. Activity-dependent BDNF release from hippocampal mossy fibers activates slowly developing inward TRPC currents in postsynaptic CA3 pyramidal neurons (Amaral and Pozzo-Miller J Neurosci 2007; Li et al. J Neurophysiol 2010). The amplitudes of TRPC currents and their associated Ca2+ transients are useful biological indicators of the releasable BDNF pool within presynaptic mossy fibers. Using this novel bioassay, we found that TRPC currentsand Ca2+ transients evoked in CA3 interneurons by mossy fiber stimulation are significantly smaller in Mecp2 mutant mice, indicating impaired activity-dependent BDNF release. We are currently testing whether BDNF mimetics and TrkB activators activate TRPC currents and Ca2+ transients similar to those induced by BDNF, as potential therapeutic interventions to restore GABAergic interneuron function and E/I balance in area CA3. Collectively, these findings define new features of Mecp2 mutant mice that may contribute to Rett pathophysiology and aid to develop novel interventions for the cure of this devastating disorder.