Presynaptic cGMP sets synaptic strength in the striatum and is important for motor learning.

The striatum is a subcortical brain region responsible for the initiation and termination of voluntary movements. Striatal spiny projection neurons receive major excitatory synaptic input from neocortex and thalamus, and cyclic nucleotides have long been known to play important roles in striatal function. Yet, the precise mechanism of action is unclear. Here, we combine optogenetic stimulation, 2‐photon imaging, and genetically encoded scavengers to dissect the regulation of striatal synapses in mice. Our data show that excitatory striatal inputs are tonically depressed by phosphodiesterases (PDEs), in particular PDE1. Blocking PDE activity boosts presynaptic calcium entry and glutamate release, leading to strongly increased synaptic transmission. Although PDE1 degrades both cAMP and cGMP, we uncover that the concentration of cGMP, not cAMP, controls the gain of striatal inputs. Disturbing this gain control mechanism in vivo impairs motor skill learning in mice. The tight dependence of striatal excitatory synapses on PDE1 and cGMP offers a new perspective on the molecular mechanisms regulating striatal activity. Synopsis: The strength of striatal input synapses is controlled by the activity of phosphodiesterases and cGMP. Disturbing this gain control mechanism in corticostriatal synapses impairs motor learning in mice. Inhibiting phosphodiesterases boosts transmission at cortico‐ and thalamostriatal synapses.This effect is mediated by presynaptic cGMP‐ and not cAMP‐signaling.Disrupting presynaptic cGMP in corticostriatal synapses impairs motor learning on the rotarod. [ABSTRACT FROM AUTHOR]