<i>Mecp2</i>Deletion from Cholinergic Neurons Selectively Impairs Recognition Memory and Disrupts Cholinergic Modulation of the Perirhinal Cortex

Abstract

Rett Syndrome is a neurological disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) and characterized by severe intellectual disability. The cholinergic system is a critical modulator of cognitive ability and is affected in patients with Rett Syndrome. To better understand the importance of MeCP2 function in cholinergic neurons, we studied the effect of selective <i>Mecp2</i> deletion from cholinergic neurons in mice. Mice with <i>Mecp2</i> deletion from cholinergic neurons were selectively impaired in assays of recognition memory, a cognitive task largely mediated by the perirhinal cortex (PRH). Deletion of <i>Mecp2</i> from cholinergic neurons resulted in profound alterations in baseline firing of L5/6 neurons and eliminated the responses of these neurons to optogenetic stimulation of cholinergic input to PRH. Both the behavioral and the electrophysiological deficits of cholinergic <i>Mecp2</i> deletion were rescued by inhibiting ACh breakdown with donepezil treatment.