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

doi:10.1016/j.celrep.2024.114540

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

Neuroscience

Research output: Contribution to journal › Article › peer-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 Ca_V1.3 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 language	English (US)
Article number	114540
Journal	Cell reports
Volume	43
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2024.114540
State	Published - 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

Access to Document

10.1016/j.celrep.2024.114540

Cite this

Zhai, S., Otsuka, S., Xu, J., Clarke, V. R. J., Tkatch, T., Wokosin, D., Xie, Z., Tanimura, A., Agarwal, H. K., Ellis-Davies, G. C. R., Contractor, A., & Surmeier, D. J. (2024). Ca²⁺-dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses. Cell reports, 43(8), Article 114540. https://doi.org/10.1016/j.celrep.2024.114540

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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.",

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",

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

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AU - Zhai, Shenyu

AU - Otsuka, Shintaro

AU - Xu, Jian

AU - Clarke, Vernon R.J.

AU - Tkatch, Tatiana

AU - Wokosin, David

AU - Xie, Zhong

AU - Tanimura, Asami

AU - Agarwal, Hitesh K.

AU - Ellis-Davies, Graham C.R.

AU - Contractor, Anis

AU - Surmeier, D. James

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AB - 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.

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