Ca2+-dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses.

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]