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Single cell profiling of the mouse striatum across dorsal-ventral subregions and following chronic clozapine administration

ABSTRACT: The ventral striatum is posited as a preferential site of antipsychotic action; while acute administration of typical antipsychotics (those associated with extrapyramidal side effects) induces intermediate early gene (IEG) expression in the dorsal striatum, acute administration of atypical antipsychotics preferentially induces IEG expression in the ventral striatum. However, cell type and regional-specific transcriptional changes in striatum in response to antipsychotics remain poorly understood. We dosed the atypical antipsychotic clozapine on an escalating schedule for six weeks to mimic human administration, and characterized transcriptional effects in the mouse striatum across cell types and subregion (dorsal versus ventral) using single nucleus RNA-sequencing (snRNA-seq).

ORGANISM(S): Mus musculus

PROVIDER: GSE294239 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Schizophrenia is a chronic mental illness that is among the world’s top twenty causes of years lost to disability according to the global burden of disease 2019 (10.1016/S0140-6736(20)30925-9). Positive symptoms, including hallucinations and delusions in schizophrenia, often improved with conventional antipsychotic medication, which exerts its therapeutic effects mainly by antagonizing the dopamine D2 receptors. Haloperidol was one of the first antipsychotics to be approved by the FDA, and it is since then widely used for the treatment of psychotic disorders including schizophrenia. Despite its high affinity for dopamine D2 receptors, it has been shown that haloperidol interacts with other receptors, such as dopamine D3 and D4 receptors, α-adrenergic receptor 1 and to some extent 5HT2A. Dopaminergic dysfunction is known for decades to be involved in the pathophysiology of schizophrenia, but only recently has the striatum been implicated in such devasting disorder. The dorsal striatum is a brain region involved in motor, cognitive and motivational functions, highly impacted by antipsychotic drugs. Particularly, it is well-recognized that chronic haloperidol administration has a tremendous impact on striatal synaptic plasticity, by changing the volume of dorsal striatum, the number of striatal neurons and the synaptic morphology, both in humans and rodents. Despite the overwhelming evidence correlating chronic haloperidol administration with striatum alterations, so far, the exact striatal synaptic mechanism by which haloperidol exerts its beneficial effects remains unclear. Although dopamine D2 receptor blockade can be achieved within hours after haloperidol administration, the onset of action is delayed by weeks. Thus, it is crucial to better understand the neuronal mechanism behind the delayed clinical effects of haloperidol to improve the treatment outcome. Using proteomic analysis and whole-cell patch-clamp recordings (Figure 1), we demonstrate for the first time a possible mechanism by which haloperidol may be contributing to its beneficial long-term therapeutic effect. Specifically, we demonstrate that modulation of D2-MSNs by chronic haloperidol administration leads to a slow remodeling of D1-neurons that may be responsible for its positive therapeutic effects.

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Single cell profiling of the mouse striatum across dorsal-ventral subregions and following chronic clozapine administration

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