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Background <p>Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. <i>Pitx3</i>-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs.</p> Methods <p>We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in <i>Pitx3</i>-deficient and control mice. Three patch SPN reporter lines (<i>Kremen1</i><sup>2A − Cre</sup>, <i>Nr4a1</i>-<i>GFP</i>, and <i>Pdyn</i><sup>IRES−Cre</sup>) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs.</p> Results <p><i>Pitx3-</i>deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the <i>Pitx3-</i>deficient group. Accordingly, patch dSPN projections to the <i>substantia nigra pars reticulata</i> (SNr) were reduced, whereas patch iSPN projections to the <i>globus pallidus externus</i> (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in <i>Pitx3</i>-deficient mice.</p> Conclusions <p>Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in <i>Pitx3</i>-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.</p>

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Developmental dopamine loss rewires striatal circuits to promote locomotion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Jie Dong,
  • Breanna T. Sullivan,
  • Victor M. Martinez Smith,
  • Lupeng Wang,
  • Lulu Tian,
  • Justin Kung,
  • Bin Song,
  • Shirong Lin,
  • Andreanna Le,
  • Lixin Sun,
  • Lisa Chang,
  • Jinhui Ding,
  • Weidong Le,
  • Jun Jia,
  • Huaibin Cai

摘要

Background

Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs.

Methods

We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen12A − Cre, Nr4a1-GFP, and PdynIRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs.

Results

Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice.

Conclusions

Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.