TY - JOUR T1 - <em>Mecp2</em> deletion from cholinergic neurons selectively impairs recognition memory and disrupts cholinergic modulation of the perirhinal cortex JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0134-19.2019 SP - ENEURO.0134-19.2019 AU - Elizabeth C Ballinger AU - Christian P Schaaf AU - Akash J Patel AU - Antonia de Maio AU - Huifang Tao AU - David A Talmage AU - Huda Y Zoghbi AU - Lorna W Role Y1 - 2019/09/27 UR - http://www.eneuro.org/content/early/2019/09/27/ENEURO.0134-19.2019.abstract N2 - 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 Mecp2 deletion from cholinergic neurons in mice. Mice with Mecp2 deletion from cholinergic neurons were selectively impaired in assays of recognition memory, a cognitive task largely mediated by the perirhinal cortex (PRH). Deletion of Mecp2 from cholinergic neurons resulted in profound alterations in baseline firing of L5/6 neurons and eliminated responses of these neurons to optogenetic stimulation of cholinergic input to PRH. Both the behavioral and the electrophysiological deficits of cholinergic Mecp2 deletion were rescued by inhibiting ACh breakdown with donepezil treatment.SIGNIFICANCE STATEMENT Rett syndrome, a developmental disorder characterized by multiple deficits including intellectual disability, is caused by mutations in the MECP2 gene. In this study, Mecp2 was selectively deleted from cholinergic neurons in mice causing a specific impairment of recognition memory that was reversed following chronic administration of the acetylcholinesterase inhibitor, donepezil. As recognition memory engages the perirhinal cortex, we examined the effects of Mecp2 deletion from cholinergic neurons on the physiology of perirhinal cortical neurons and found a reduction in variability of baseline firing and impaired responsiveness to optogenetic stimulation of cholinergic input. Our findings are consistent with a loss of encoding capacity in the perirhinal cortex and suggest a possible electrophysiological substrate for the altered profile of recognition memory performance. ER -