Ca2+-dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses

Shenyu Zhai, Shintaro Otsuka, Jian Xu, Vernon R.J. Clarke, Tatiana Tkatch, David Wokosin, Zhong Xie, Asami Tanimura, Hitesh K. Agarwal, Graham C.R. Ellis-Davies, Anis Contractor, D. James Surmeier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Our studies reveal that SPNs manifest a heterosynaptic, nitric oxide (NO)-dependent form of long-term postsynaptic depression of glutamatergic SPN synapses (NO-LTD) that is preferentially engaged at quiescent synapses. Plasticity is gated by Ca2+ entry through CaV1.3 Ca2+ channels and phosphodiesterase 1 (PDE1) activation, which blunts intracellular cyclic guanosine monophosphate (cGMP) and NO signaling. Both experimental and simulation studies suggest that this Ca2+-dependent regulation of PDE1 activity allows for local regulation of dendritic cGMP signaling. In a mouse model of Parkinson disease (PD), NO-LTD is absent because of impaired interneuronal NO release; re-balancing intrastriatal neuromodulatory signaling restores NO release and NO-LTD. Taken together, these studies provide important insights into the mechanisms governing NO-LTD in SPNs and its role in psychomotor disorders such as PD.

Original languageEnglish (US)
Article number114540
JournalCell reports
Volume43
Issue number8
DOIs
StatePublished - Aug 27 2024

Keywords

  • CP: Neuroscience
  • L-type Ca channel
  • Parkinson's disease
  • autism
  • cGMP
  • low-threshold spiking interneuron
  • nitric oxide
  • phosphodiesterase
  • spiny projection neuron
  • striatum
  • synaptic plasticity

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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