In this study, we show that dopamine depletion causes a target-specific reorganization of the feedforward inhibitory circuit through selective enhancement of FS connections to D2 MSNs. A simple model of the striatal microcircuit suggests

that this pathway-specific increase in connectivity is sufficient to augment firing synchrony between indirect-pathway projection neurons, thus implicating reorganization of FS microcircuits in striatal Enzalutamide dysfunction in PD. In the striatum of 6-OHDA-injected mice, we find that dopamine depletion causes an increase in FS innervation of D2 MSNs, driven by sprouting of FS axons. This was confirmed anatomically by reconstructions of FS interneurons and immunohistological analysis of presynaptic puncta, and functionally by paired recordings showing increased FS-D2 MSN connectivity and increased mIPSC frequency selectively in D2 MSNs. These results demonstrate that dopamine depletion can induce a target-specific remodeling

of FS innervation, which is both rapid (observed within 3 days) and persistent (observed at 4 weeks). This target-specific plasticity may represent a homeostatic response to D2 MSN hyperactivity after dopamine depletion. Within hours to days after dopamine depletion, D2 MSNs this website show increased excitability (Fino et al., 2007, Mallet et al., 2006 and Nicola et al., 2000), accompanied by reduced spine density (Day et al., 2006) and collaterals between both MSN subtypes (Taverna et al., 2008). The hyperactivity of MSNs in the indirect pathway could trigger

compensatory upregulation of inhibition from FS 3-mercaptopyruvate sulfurtransferase interneurons, reminiscent of compensatory sprouting observed by some types of GABAergic interneurons in epilepsy (Bausch, 2005, Davenport et al., 1990, Klaassen et al., 2006 and Palop et al., 2007). Indeed, previous studies have demonstrated that structural plasticity of GABAergic interneurons can occur within hours or days (Chen et al., 2011 and Marik et al., 2010). The mechanisms of compensatory sprouting of inhibitory axons have long remained enigmatic (Valdes et al., 1982). In the hippocampus a subset of inhibitory inputs is selectively strengthened by reductions in endocannabinoid (eCB) signaling (Kim and Alger, 2010), and in the striatum, reduced eCB-dependent LTD in D2 MSNs is thought to contribute to increased drive on the indirect pathway following dopamine depletion (Kreitzer and Malenka, 2007). However, it does not appear that eCBs in the striatum contribute to compensatory sprouting of FS interneurons because we did not observe changes in amplitude and short-term plasticity of IPSCs as described by Kim and Alger, 2010. Alternatively, BDNF signaling through TrkB receptors has also been shown to regulate sprouting of inhibitory axons (Huang et al., 1999, Peng et al., 2010, Rutherford et al., 1997, Seil and Drake-Baumann, 2000 and Swanwick et al.