PMID- 35701839
OWN - NLM
STAT- MEDLINE
DCOM- 20220616
LR  - 20220716
IS  - 1756-6606 (Electronic)
IS  - 1756-6606 (Linking)
VI  - 15
IP  - 1
DP  - 2022 Jun 14
TI  - Downregulation of CDK5 signaling in the dorsal striatum alters striatal 
      microcircuits implicating the association of pathologies with circadian behavior 
      in mice.
PG  - 53
LID - 10.1186/s13041-022-00939-2 [doi]
LID - 53
AB  - Dysfunction of striatal dopaminergic circuits has been implicated in motor 
      impairment and Parkinson's disease (PD)-related circadian perturbations that may 
      represent an early prodromal marker of PD. Cyclin-dependent kinase 5 (CDK5) 
      negatively regulates dopamine signaling in the striatum, suggesting a critical 
      role of CDK5 in circadian and sleep disorders. Here, we used clustered regularly 
      interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to produce mice 
      with a dorsal striatum (DS)-specific knockdown (KD) of the Cdk5 gene (referred to 
      as DS-CDK5-KD mice) and investigate its role in vivo. DS-CDK5-KD mice exhibited 
      deficits in locomotor activity and disturbances in activity/rest behavior. 
      Additionally, Golgi staining of neurons in the DS revealed that CDK5 deletion 
      reduced dendrite length and the number of functional synapses, which was 
      confirmed by significant downregulation of MAP2, PSD-95, and synapsin I. 
      Correlated with this, DS-CDK5-KD mice displayed reduced phosphorylation of Tau at 
      Thr181. Furthermore, whole-cell patch-clamp recordings of green fluorescent 
      protein-tagged neurons in the striatum of DS-CDK5-KD mice revealed a decreased 
      frequency of spontaneous inhibitory postsynaptic currents and altered 
      excitatory/inhibitory synaptic balance. Notably, anterograde labeling showed that 
      CDK5 KD in the DS disrupted long-range projections to the secondary motor cortex, 
      dorsal and ventral thalamic nuclei, and basolateral amygdala, which are involved 
      in the regulation of motor and circadian rhythms in the brain. These findings 
      support a critical role of CDK5 in the DS in maintaining the striatal neural 
      circuitry underlying motor functions and activity/rest associated with circadian 
      rhythms that are perturbed in neurodegenerative disorders.
CI  - (c) 2022. The Author(s).
FAU - Zhou, Hu
AU  - Zhou H
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China.
FAU - Zhang, Jingxin
AU  - Zhang J
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China.
FAU - Shi, Huaxiang
AU  - Shi H
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China.
FAU - Li, Pengfei
AU  - Li P
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China.
FAU - Sui, Xin
AU  - Sui X
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China.
FAU - Wang, Yongan
AU  - Wang Y
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China. yonganw@163.com.
FAU - Wang, Liyun
AU  - Wang L
AUID- ORCID: 0000-0002-5253-7091
AD  - State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute 
      of Pharmacology and Toxicology, Beijing, 100850, China. lylywang1103@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220614
PL  - England
TA  - Mol Brain
JT  - Molecular brain
JID - 101468876
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - *Circadian Rhythm
MH  - Corpus Striatum/metabolism
MH  - *Cyclin-Dependent Kinase 5/metabolism
MH  - Dopamine
MH  - Down-Regulation
MH  - Mice
MH  - Synapses/metabolism
PMC - PMC9195255
OTO - NOTNLM
OT  - Circadian behavior
OT  - Cyclin-dependent kinase 5 (CDK5)
OT  - Dorsal striatum (DS)
OT  - Motor activity
OT  - Neuronal projections
COIS- The authors declare no competing financial interests.
EDAT- 2022/06/15 06:00
MHDA- 2022/06/18 06:00
PMCR- 2022/06/14
CRDT- 2022/06/14 23:42
PHST- 2021/12/18 00:00 [received]
PHST- 2022/05/27 00:00 [accepted]
PHST- 2022/06/14 23:42 [entrez]
PHST- 2022/06/15 06:00 [pubmed]
PHST- 2022/06/18 06:00 [medline]
PHST- 2022/06/14 00:00 [pmc-release]
AID - 10.1186/s13041-022-00939-2 [pii]
AID - 939 [pii]
AID - 10.1186/s13041-022-00939-2 [doi]
PST - epublish
SO  - Mol Brain. 2022 Jun 14;15(1):53. doi: 10.1186/s13041-022-00939-2.