Hippocampal Slices from MECP2 Null Mice are Hyperexcitable and Prone to Epileptiform Activity: A Voltage-Sensitive Dye Study

CALFA GD, HABLITZ JJ, POZZO-MILLER L

Chicago

Congreso; 9th Annual Rett Syndrome Symposium, International Rett Syndrome Foundation (IRSF); 2008

IRSF

Rett Syndrome (RTT) is a mental retardation-associated neurodevelopmental disorder caused by mutations in the gene encoding for MeCP2, a transcriptional repressor that binds to methylated DNA. It has been hypothesized that the miswiring of CNS synapses during brain development in RTT patients impairs those synaptic functions that underlie cognitive abilities and adaptive behaviors. Consistent with such postulated synaptic misregulation, partial and generalized convulsive or silent (i.e. absence) seizures are a common clinical manifestation in RTT patients. Based on intracellular recordings from individual hippocampal and cortical pyramidal neurons, prior studies have postulated that MECP2 deficiency leads to an imbalance of excitatory and inhibitory synaptic activities favoring network inhibition. Considering that multiple mechanisms may contribute to the finely excitatory and inhibitory balance, we imaged network activity in hippocampal slices of MECP2-null mice using a fluorescent voltage-sensitive dye (RH-414) and an array of fast-responding photodiodes. Single 200-μsec afferent stimulation of the associational/Shaffer collateral pathway evoked voltage-dye signals in CA1 stratum radiatum that were significantly (>20%) longer and more widespread in slices from symptomatic MECP2-null mice compared to slices from wildtype littermates (postnatal day 45-50). In addition, MECP2-null slices showed significantly (>50%) longer and more widespread voltage dye signals after K+ channel blockade with 4-AP (125mM) than wildtype slices. These experimental observations indicate that MECP2 deficiency indeed causes an imbalance of excitatory and inhibitory synaptic activities, but favoring network hyperexcitability as well as enhanced sensitivity to epileptogenic manipulations. Further studies of the release capabilities of excitatory and inhibitory presynaptic terminals are under investigation as potential mechanisms underlying the hyperexcitability of the hippocampal circuit in MECP2-deficient mice.