Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice we identified a narrow postnatal period characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and respond strongly to cortical afferents despite sparse excitatory inputs. As a result, striatum and corticostriatal connectivity are highly sensitive to acute and chronic changes in cortical activity, suggesting that early imbalances in cortical function alter BG development. Indeed, a mouse model of autism with deletions in SHANK3 (Shank3B−/−) has early cortical hyperactivity, which triggers increased SPN excitatory synapse and corticostriatal hyper-connectivity. These results show a tight functional coupling between cortex and striatum during early postnatal development and suggest a potential common circuit dysfunction caused by cortical hyperactivity.

The striatum regulates motor control, reward, and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G-protein-coupled receptor (GPCR) GPR88 is robustly expressed in MSNs and regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. Here we show that in the absence of GPR88, MSNs have increased glutamatergic excitation and reduced GABAergic inhibition that together promote enhanced firing rates in vivo, resulting in hyperactivity, poor motor-coordination, and impaired cue-based learning in mice. Targeted viral expression of GPR88 in MSNs rescues the molecular and electrophysiological properties and normalizes behavior, suggesting that aberrant MSN activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.

In the basal ganglia (BG), anatomically segregated and topographically-organized feedforward circuits are thought to modulate multiple behaviors in parallel. Although topographically-arranged BG circuits have been described, the extent to which these relationships are maintained across the BG output nuclei and in downstream targets is unclear. Here, using focal transsynaptic anterograde tracing, we show that the motor-action related topographical organization of the striatum is preserved in all BG output nuclei. The topography is also maintained downstream of the BG and in multiple parallel closed loops that provide striatal input. Furthermore, focal activation of two distinct striatal regions induce either licking or turning, consistent with the structure of projections to targets outside the BG. Our results confirm the parallel model of BG function, and suggest that the integration and competition of information relating to different behavior occurs largely outside of the BG.