Downregulation of CDK5 Signaling In the Dorsal Striatum Alters Striatal Microcircuits and Perturbs Circadian Behavior in Mice

Abstract

Dysfunction of striatal dopaminergic circuits has been implicated in motor impairment as well as in Parkinson’s disease (PD)-related circadian perturbations that may represent an early prodromal marker of PD. Cyclin-dependent kinase 5 (CDK5) acts negatively on dopamine (DA) signaling in the striatum, suggesting a critical role in circadian and sleep disorders. Here, we used CRISPR/Cas9 gene editing to produce dorsal striatum (DS)-specific knockdown (KD) of the Cdk5 gene in mice (referred to as DS-CDK5-KD mice) to investigate its role in vivo. DS-CDK5-KD mice exhibited deficits in locomotor activity and disturbances in daily rest/activity cycles. Additionally, Golgi staining of neurons in the DS revealed that Cdk5 deletion caused a reduction in dendrite length and functional synapses, which was confirmed by significant downregulation of MAP2, PSD95 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 (GFP)-tagged neurons in the striatum of DS-CDK5-KD mice revealed a decrease in the frequency of spontaneous inhibitory post-synaptic currents and an alteration of the excitatory/inhibitory synaptic balance. Notably, anterograde labeling showed that CDK5 knockdown in the DS disrupted long-range projections to the secondary motor cortex, dorsal and ventral thalamic nuclei, and the 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 and circadian rhythms related to PD.