Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Molecular Signaling

Background:

• The dorsolateral striatum is vital for motor learning and planning.
• Synaptic plasticity in this region is influenced by dopamine, NMDA receptors (NMDAR), and CaMKII.
• The role of protein kinase Cdk5 in cortico-striatal plasticity remains incompletely understood.

Purpose of the Study:

• To establish a method for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuits.
• To determine the contributions of neurotransmitter receptors and intracellular signaling molecules, specifically Cdk5, to this plasticity.
• To link molecular plasticity mechanisms to behavioral outcomes in motor learning.

Main Methods:

• Developed an approach to study synaptic plasticity in the mouse dorsolateral striatum.
• Utilized pharmacological inhibition, conditional knockout, and viral-mediated gene deletion to assess Cdk5 function.
• Measured long-term potentiation (LTP) and behavioral parameters like locomotor activity and motor learning.

Main Results:

• Dopamine-facilitated LTP in cortico-striatal circuits requires D1-dopamine receptors, NMDAR, and CaMKII.
• Impairment of Cdk5 function (pharmacologically or genetically) disrupted D1-dopamine receptor-facilitated LTP.
• Loss of Cdk5 specifically in the dorsolateral striatum led to increased locomotor activity and impaired motor learning.

Conclusions:

• Cdk5 is critically involved in cortico-striatal synaptic plasticity, alongside D1-dopamine receptors, NMDAR, and CaMKII.
• Deficits in striatal plasticity due to Cdk5 loss correlate with behavioral changes in motor control.
• The presented approach offers a valuable tool for studying the molecular underpinnings of dorsolateral striatal plasticity.