Parkin deficiency perturbs striatal circuit dynamics

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Loss-of-function mutations in the parkin gene (PARK2) are a common cause of early-onset, autosomal recessive Parkinson's disease (PD).
• Parkin knockout mice show altered striatal dopamine transmission and cortico-striatal synaptic function, but the impact on intact neural circuit dynamics is unclear.

Purpose of the Study:

• To investigate how parkin deficiency affects neural dynamics and cell-type-specific functional connectivity in the basal ganglia circuits during the presymptomatic stage of Parkinson's disease.
• To understand the impact of parkin loss on cortico-striatal oscillations and interneuron activity.

Main Methods:

• Electrophysiological recordings from the motor cortex, striatum, and globus pallidus (GP) in anesthetized parkin-deficient and control mice.
• Analysis of ongoing neuronal activity, firing rates, and oscillatory dynamics, including spike-field coupling.

Main Results:

• Parkin deficiency led to elevated activity in tonically active striatal neurons but reduced baseline firing rates and disrupted microcircuitry in fast-spiking interneurons (FSIs).
• Striatal circuits exhibited enhanced and phase-shifted coupling to slow cortical oscillations (1-3 Hz).
• Amplified beta oscillations (~22 Hz) were observed in the striatum and GP, with parkin deficiency selectively increasing FSI spike-field coupling to these beta oscillations.

Conclusions:

• Loss of parkin function causes amplification of synchronized cortico-striatal oscillations and reconfigures intrastriatal interneuronal circuits.
• These presymptomatic disruptions in dynamic functional connectivity may precede nigro-striatal neurodegeneration and contribute to the imbalance of striatal outflow seen in symptomatic PD.