CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntingtons disease and levodopa-induced dyskinesia in Parkinsons disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the selfadministration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGIs therapeutic potential. Funding Agencies: William N. & Bernice E. Bumpus Foundation; Saks Kavanaugh Foundation; Simons Foundation; National Institute of Child Health and Development United States Department of Health & Human Services National Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [R37 HD028341]; James and Pat Poitras Research Fund; Stanley Center for Psychiatric Research at the Broad Institute; National Institute of Mental Health United States Department of Health & Human Services National Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH071847, F32 MH065815]; National Institute on Aging United States Department of Health & Human Services National Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [R01 AG050548]; European Community FP7 - The-matic priority HEALTH contract [222918]; Ministry of Health; JPB Foundation; National Institute on Drug Abuse United States Department of Health & Human Services National Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) European Commission [R00 DA027825, R01 DA07418]