Dopamine D2 Receptors Regulate the Anatomical and Functional Balance of Basal Ganglia Circuitry

Abstract

Summary Structural plasticity in the adult brain is essential for adaptive behavior. We have found a remarkable anatomical plasticity in the basal ganglia of adult mice that is regulated by dopamine D2 receptors (D2Rs). By modulating neuronal excitability, striatal D2Rs bi-directionally control the density of direct pathway collaterals in the globus pallidus that bridge the direct pathway with the functionally opposing indirect pathway. An increase in bridging collaterals is associated with enhanced inhibition of pallidal neurons in vivo and disrupted locomotor activation after optogenetic stimulation of the direct pathway. Remarkably, chronic blockade with haloperidol, an antipsychotic medication used to treat schizophrenia decreases the extent of bridging collaterals and rescues the locomotor imbalance. These findings identify a role for bridging collaterals in regulating the concerted balance of striatal output, and may have important implications for understanding schizophrenia, a disease involving excessive activation of striatal D2Rs that is treated with D2R blockers.

Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine

“…Similarly, striatal GABAergic interneurons do not express D2Rs; furthermore, in D2RKO and MSN-D2RKO mice, these neurons likely receive lower cortical stimulation because of the lack of inhibition of iMSNs activity on the indirect pathway. The full rescue of c-fos induction by GABA antagonism supports the view of a major intrastriatal effect of iMSNs on dMSNs via collaterals (17,27). We propose that deletion of D2R specifically in iMSNs is at the basis of the inhibition of signaling in dMSNs after cocaine.…”

The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think

“…Thus, these D2-MSNs make a direct pathway through the VP that disinhibits the thalamus. These findings are not restricted to the ventral striatum as other emerging studies have observed similar results in the dorsal striatum (Cazorla et al, 2014;Saunders et al, 2015).…”

Communication in Neural Circuits: Tools, Opportunities, and Challenges

“…Many discussions of the function of the BG to date have relied on the simple concept of a “direct” and an “indirect” pathway offering two alternative, opposing streams of information flow from the input nucleus of the BG (striatum) to the output nucleus (SNr; Figure 5A). Yet reality is well known to be substantially more complex, involving multiple feedback loops and spirals among nuclei (Figures 5B–D; Alexander et al, 1986; Cazorla et al, 2014; Haber, 2003; Kupchik et al, 2015; Mallet et al, 2012; Nambu et al, 2002; Saunders et al, 2015). The richness of this structure is both enticing and intimidating; there are clearly many more discoveries to be made about BG circuit function, yet already the complexity of our simplified diagram makes forming an intuitive understanding of circuit dynamics (and hence experimental design and data interpretation) very difficult.…”