DARPP-32 and dopamine signaling: implications for neuropsychiatric disorders, motor function, and therapeutic modulation

Dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), encoded by the PPP1R1B gene, functions as a pivotal signaling hub that translates dopaminergic input into downstream cellular responses. Phosphorylation of DARPP-32 at multiple sites determines its dual role as either an inhibitor or facilitator of protein phosphatase-1, thereby fine-tuning neuronal excitability, synaptic plasticity, and gene expression. This bidirectional regulation makes DARPP-32 essential for maintaining the balance between D1- and D2-receptor-mediated signaling in striatal and cortical circuits.

Altered DARPP-32 activity has been implicated in a spectrum of dopamine-related conditions, including schizophrenia, bipolar disorder, Parkinson’s disease, and drug addiction, where dysregulated dopaminergic tone disrupts signal integration and behavioral control. Beyond its canonical role in striatal neurons, DARPP-32 also participates in memory formation and synaptic plasticity, linking dopaminergic modulation to cognitive processes. DARPP-32 is identified as both a biomarker and a potential therapeutic target. Its phosphorylation state reflecting treatment response to antipsychotics, dopaminergic drugs, and novel neuromodulators.

Collectively, DARPP-32 represents a molecular interface where neurotransmission, intracellular signaling, and behavioral outcomes converge, offering new opportunities to understand and modulate dopamine-dependent pathologies.

This collection invites original research articles, reviews, and perspectives that advance understanding of DARPP-32 as a central mediator of dopamine signaling in health and disease. DARPP-32 acts as a molecular switch that integrates dopaminergic, glutamatergic, and serotonergic inputs to regulate neuronal excitability, synaptic plasticity, and transcriptional responses. Alterations in its phosphorylation dynamics and signaling interactions have been linked to multiple brain disorders, making it a promising molecular entry point for therapeutic discovery.

The scope of this collection encompasses studies that explore the biochemical, molecular, behavioral, and therapeutic dimensions of DARPP-32, including but not limited to:

• Mechanistic insights into DARPP-32 phosphorylation, signaling networks, and receptor cross-talk (D1/D2 pathways, PKA/PP1 regulation).

• Roles of DARPP-32 in psychiatric disorders such as schizophrenia, bipolar disorder, and depression.

• Movement disorders and Parkinson’s disease, focusing on DARPP-32’s contribution to dopaminergic dysregulation, motor control, and L-DOPA-induced dyskinesia.

• Addiction and substance use—DARPP-32 as a mediator of reward circuitry and drug reinforcement.

• Involvement in memory formation, synaptic plasticity, and learning through dopaminergic modulation of cortical-striatal circuits.

• Emerging drug targets and biomarkers, including pharmacological, genetic, and molecular approaches that modulate DARPP-32-related pathways to improve therapeutic efficacy or reduce adverse drug effects.

Through this collection, we aim to bring together interdisciplinary research bridging neuroscience, pharmacology, psychiatry, and molecular signaling, fostering new perspectives on how DARPP-32 serves as a unifying node in dopaminergic regulation of brain function and behavior.

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• Data Report
• Editorial
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• General Commentary
• Hypothesis and Theory
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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: DARPP-32, dopamine signaling, phosphorylation, neuropsychiatric disorders, synaptic plasticity, motor function, therapeutic target, striatal circuits, biomarker, gene expression

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.