Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors

Abstract

The direct and indirect pathways of the basal ganglia have been proposed to oppositely regulate locomotion and differentially contribute to pathological behaviors. Analysis of the distinct contributions of each pathway to behavior has been a challenge, however, due to the difficulty of selectively investigating the neurons comprising the two pathways using conventional techniques. Here we present two mouse models in which the function of striatonigral or striatopallidal neurons is selectively disrupted due to cell typespecific deletion of the striatal signaling protein dopamine-and cAMP-regulated phosphoprotein Mr 32kDa (DARPP-32). Using these mice, we found that the loss of DARPP-32 in striatonigral neurons decreased basal and cocaine-induced locomotion and abolished dyskinetic behaviors in response to the Parkinson's disease drug L-DOPA. Conversely, the loss of DARPP-32 in striatopallidal neurons produced a robust increase in locomotor activity and a strongly reduced cataleptic response to the antipsychotic drug haloperidol. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors.basal ganglia | DARPP-32 | locomotor behavior | striatonigral | striatopallidal T he basal ganglia (BG) are subcortical structures that coordinate vital behaviors including movement, reward, and motivational processes (1). BG dysfunction is associated with several human diseases, including Parkinson's disease (PD), schizophrenia, and drug addiction. The striatum receives the majority of input into the BG, and projects to the output nuclei of the BG via two pathways that work together to modulate behavior: the D1 receptor (D1R)-expressing direct pathway, which projects to the substantia nigra pars reticulata (SNpr), and the D2 receptor (D2R)-expressing indirect pathway, which projects to the medial globus pallidus (GP) (2). Classical models of the BG propose that these two efferent pathways exert opposing effects on locomotor behavior (3, 4); namely, activation of the direct pathway increases locomotor activity, whereas the indirect pathway exerts a tonic inhibitory tone. Thus, an imbalance of these two pathways would disrupt coordinated movement, resulting in hypokinetic or hyperkinetic movement disorders (3). Direct confirmation of these hypotheses has been hindered by difficulty in selectively targeting direct and indirect pathway neurons with traditional surgical and pharmacological techniques.An understanding of the differential contribution of the direct and indirect pathways to behavior is essential for generating more selective therapies for BG-related disorders. This would be especially valuable in the case of PD and schizophrenia, where motor complications can result from pharmacological treatment. For example, the positive symptoms of schizophrenia are effectively treated with typical antipsychotic drugs, such as haloperidol; however, these drugs are often associated with extrapyramidal side effects including catalepsy, manifested as extreme hypolocomoti...

Selective Deletion of GRK2 Alters Psychostimulant-Induced Behaviors and Dopamine Neurotransmission

“…These results argue against any contribution of BAC transgene expression or integration site to DArelated phenotypes in these animals and are consistent with other published observations using these BAC transgenic animals (Bateup et al, 2010;Guzman et al, 2011).…”

“…Enhanced DARPP-32 Signaling in the Striatum of Cocaine-Treated D1R cre Grk2 f/f Mice To determine whether the hypersensitivity phenotype of D1R cre Grk2 f/f mice was accompanied by alterations in striatal signaling, we next analyzed phospho-DARPP-32 levels because (1) cocaine has been shown to increase the phosphorylation of DARPP-32 at threonine 34 (T34) selectively in striatonigral neurons (Bateup et al, 2008) and Role of GRK2 in the brain dopamine system TL Daigle et al (2) because DARPP-32 regulates basal and cocaine-induced locomotion (Bateup et al, 2010). Here we observed that acute cocaine administration promoted a robust increase in striatal pT34 DARPP-32 levels in both genotypes (interaction, F (1,17) ¼ 34.47, po0.0001); however, the effect was significantly enhanced in D1R cre Grk2 f/f mice relative to control animals (210 ± 11% vs 149 ± 17% of control, respectively; interaction, F (1,17) ¼ 5.06, p ¼ 0.03; Figure 3a).…”

“…Previous work from our lab also suggests that striatal D2 receptors signal in a G-protein-independent manner via the scaffolding protein barrestin-2 to modulate striatal protein kinase B (Akt) and GSK3b signaling Beaulieu et al, 2007). Genetic and/or pharmacological disruption of downstream effectors engaged by DA receptors (eg, DA-and cAMP-regulated phosphoprotein of molecular weight 32 kDa and GSK3b) robustly alters motor behavior and sensitivity to antipsychotic and psychostimulant drugs (Bateup et al, 2010;Beaulieu et al, 2004;Urs et al, 2012). Thus, a more comprehensive understanding of proteins involved in DA receptor signaling may yield valuable mechanistic insights regarding several important clinically relevant drugs and provide novel therapeutic targets.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…It is most often used in the sense that the basal ganglia play a role in making the most appropriate action for a given situation by selecting the optimal response and blocking competing ones [24]. The general concept that activation of the direct pathway facilitates movement, while activation of the indirect pathway reduces movement, is supported by recent optogenetic studies [25][26][27]. This general framework may have pathophysiologic relevance (see below), in that hypokinetic diseases such as PD are associated with increased basal ganglia output, while hyperkinetic diseases (such as dystonia or chorea) are associated with abnormally low basal ganglia output [15,16].…”

Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

“…These pathologic circuits have been shown to develop in striatum of dopamine-denervated animals, which show a loss of dendritic spines in medium spiny GABA-ergic projection neurons. With genetic knockout strategies, subpopulations of these medium spiny neurons have been shown to mediate different behavioral effects [53]. Differential damage to medium spiny neurons may account for the dyskinetic response to L-DOPA seen in patients with Parkinson's disease.…”