# NIH grant: The role of tonic DA release in Parkinsonian motor deficits (1R01NS149758-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01NS149758-01)

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NIH grant 1R01NS149758-01: The role of tonic DA release in Parkinsonian motor deficits
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Hidehiko  Inagaki. Award: $677059.
Start: 2026-07-17T00:00:00.
Project Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic
neurons in the substantia nigra, leading to dysfunction in striatal circuit and motor deficits. Emerging evidence
suggests that defects in dopamine (DA) release contribute to early motor symptoms prior to neurodegeneration,
suggesting that dopaminergic synaptic dysfunction is a hallmark of early PD. Intriguingly, mice lacking
Synaptotagmin-1 in DA neurons (Syt-1DA cKO), which abolishes phasic but not tonic (basal/spontaneous firing)
DA release, do not develop motor deficits or DA neuron degeneration. These recent findings suggest that not all
forms of dysregulated DA release leads to motor deficits, and that tonic DA release may be critical for maintaining
motor function. The goal of this proposal is to define the molecular basis and network consequences of DA
release deficits that impair motor control by leveraging a PD-relevant genetic model. Synj1 (encoding
Synaptojanin1) is a lipid phosphatase essential for synaptic vesicle (SV) endocytosis. Our recent studies found
that Synj1 not only regulates SV recycling but also the recycling of surface proteins, such as the dopamine
transporter (DAT) and dopamine D2 short autoreceptors (D2S) by inhibiting PKC signaling. The reuptake
activity of DAT enables DA storage in SVs, and the released DA further activates D2S to regulate DAT function.
We hypothesize that these key molecular components and their feedback regulation are essential for tonic DA
release, which are disrupted in Synj1 deficient conditions, leading to striatal circuit dysfunction and locomotor
deficits. Supporting this hypothesis, we found that Synj1DA cKO mice exhibit robust locomotor deficits, loss of
striatal DAT expression, and reduced DA storage at an early age without significant loss of axonal markers like
TH. Thus, this model offers a unique opportunity for us to assess the role of DA release defects in motor control
without complications of neurodegeneration. In Aim 1, we will employ functional imaging to investigate the
mechanistic basis of tonic DA release at the single bouton level in cultured neurons and determine whether
suppressing PKC rescues DA release defects. In Aim 2 we will take a systems approach to investigate striatal
DA, spiking dynamics and behavior in head-fixed awake Synj1DA cKO mice performing a licking task. We will
also determine whether suppressing PKC can improve these abnormalities. Given that DAT dysfunction is
common across genetic and idiopathic forms of PD, the insights gained from this work and the therapeutic
potential of targeting PKC may have broad translational impact for functional recovery in early PD.
```



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