ABSTRACT The basal ganglia circuitry ? including the primary input nucleus, the striatum ? critically regulates numerous behavioral processes and is implicated in the pathophysiology of multiple neuropsychiatric conditions, including Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Regulation of the basal ganglia by the modulatory neurotransmitter dopamine (DA) has been extensively studied. Much less is known about the regulation of this circuitry by histamine (HA). Recent findings have highlighted the contribution of dysregulated HA modulation of the basal ganglia to neuropsychiatric disease, especially TS and OCD. A mutation in histidine decarboxylase (Hdc), the key biosynthetic enzyme required for HA production, was identified as a rare cause of TS and, with lower penetrance, of OCD. Our studies in Hdc knockout mice confirm that HA disruption can lead to TS-relevant behaviors and changes in striatal neurochemistry and function. Preliminary data from the mouse model focus attention on the histamine receptor H3R, which is highly expressed in the striatum. Signaling by H3R in the basal ganglia is not well understood. Recent work, most of it ex vivo, has documented heterodimerization between H3R and both D1R and D2R dopamine receptors and shown that H3R and D1R interact in counterintuitive ways in the regulation of MAPK. Such heterodimerization of G- protein-coupled receptors is increasingly reported, but its functional significance has been difficult to pin down. We have replicated H3R-D1R functional interactions in vivo and identified a behavioral correlate. We have also identified a novel, cell-type specific effect of H3R on signaling through AKT-GSK3?: in striatal medium spiny neurons that express D1R (D1R-MSNs), H3R leads to phosphorylation (and thus inactivation) of GSK3?, while in D2R-MSNs it leads to GSK3? dephosphorylation. This differential regulation of both MAPK and GSK3? highlights the ability of H3R-DR functional interactions to modulate signaling and the importance of better understanding this dimension of striatal regulation. We propose to use existing transgenic mouse lines to characterize functional interactions between H3R and dopamine receptors in D1R- and D2R-MSNs of the dorsal striatum. We predict nonlinear interactions in the regulation of both MAPK and GSK3?, and that these will lead to interactions in the regulation of locomotor activity. We will test the causal importance of H3Rs in specific striatal cell types by generating inducible H3R knockout mice, which we will cross with cell type-specific cre-expressing transgenic mice to produce D1R- and D2R-MSN-specific disruption of H3R signaling. We predict differential effects at the level of both signaling and behavior when H3R is disrupted in different MSN subtypes. These experiments will shed new light on the underappreciated role of HA in the modulation of basal ganglia function and lay the groundwork for future studies in animal models of pathophysiology.