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Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Our studies reveal that SPNs manifest a heterosynaptic, nitric oxide (NO)-dependent form of long-term postsynaptic depression of glutamatergic SPN synapses (NO-LTD) that is preferentially engaged at quiescent synapses. Plasticity is gated by Ca2+ entry through Ca V 1.3 Ca2+ channels and phosphodiesterase 1 (PDE1) activation, which blunts intracellular cyclic guanosine monophosphate (cGMP) and NO signaling. Both experimental and simulation studies suggest that this Ca2+-dependent regulation of PDE1 activity allows for local regulation of dendritic cGMP signaling. In a mouse model of Parkinson disease (PD), NO-LTD is absent because of impaired interneuronal NO release; re-balancing intrastriatal neuromodulatory signaling restores NO release and NO-LTD. Taken together, these studies provide important insights into the mechanisms governing NO-LTD in SPNs and its role in psychomotor disorders such as PD. [Display omitted] • cGMP-dependent LTD of striatal glutamatergic synapses was controlled by PDE1 • The activity of PDE1 was regulated by Ca2+ influx through Ca V 1.3 Ca2+ channels • This coupling limited cGMP-dependent LTD to dendritic regions that were inactive • Reversing neuromodulatory imbalance restored cGMP-LTD in a Parkinson's disease model Synaptic plasticity in the brain is generally considered to be dependent on elevated neuronal activity. Zhai et al. describe a heterosynaptic form of postsynaptic, long-term depression of glutamatergic synapses in striatal spiny projection neurons that is dependent on inactivity, making it a potential mechanism for "forgetting." [ABSTRACT FROM AUTHOR]

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: Huntington's disease and levodopa-induced dyskinesia in Parkinson's 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 self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential. • CalDAG-GEFI mediates M1 muscarinic receptor dependent plasticity in the striatum. • CDGI mediates dendritic, but not somatic, M1Rs signaling in striatal iSPNs. • CDGI is required for full induction of long-term synaptic potentiation in iSPNs. • Mice lacking CDGI fail to show behavioral plasticity induced by M1R agonists. • Mice lacking CDGI have increased susceptibility to drugs of abuse. [ABSTRACT FROM AUTHOR]