Research On Synapse Plasticity Mechanism In Motor Skill Learning Disability In Mice Models Of Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's (AD). The loss of midbrain dopaminergic neuron is the hallmark of PD, a condition characterized by deficits in both motor functions and motor skill learning. Most studies about PD have focued on basal ganglia, and have known the decline in movement control are linked to aberrant alterations of neural circus structure and function plasticity in basal ganglia. While the deficiencies in motor skill learning and memory ability remain largely unexplored.Primary motor cortex (M1) is the superior nerve center and controls the motor ability, proper M1 processing in synaptic plasticity and dynamic adaptations are critical for motor skill learning and maintaining memory throughout life. Research have shown that DA may serve to harmonize motor action patterns and task-related movement synergies to enable precise movements. But in DA damaged PD, researchs have shown that motor cortex functions are abnormal and chronic epidural motor cortex stimulation can improve PD symptoms. How dendritic spine dynamics and synaptic functional plasticity are altered by the loss of dopaminergic innervation during the progression of PD, whether such neuronal circuitry plasticity in motor cortex can elucidate motor skill learning disabilities in Parkinson's disease remains unkown. To address these fundamental questions, we investigate the synaptic remodeling and dynamic change regularity following dopamine depletion in the intact motor cortex by repeatedly in vivo imaging the apical dendrites of layer V pyramidal neurons through a cranial skull window in Thyl-YFP-H line transgene mice. By combining the motor skill learning with in vivo imaging, we elucidate the motor learning deficits and memory disabilities mechanism underlying Parkinson's disease.The main research contents are listed below:(1) Establishing a reliable and stable PD mouse model:We established a PD mouse model byintraperitoneal MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) injection in consecutive 4 days. Its reliability and stability was proved by immunohistochemical staining (IHC).(2) The dynamic change of dendritic spine in M1 in PD:We used different mouse models of PD and two-photon imaging to show that dopamine depletion resulted in dramatic increases in both spine elimination and formation in the motor cortex and such changes only occured in M1. The spine turnover completely unaffected in neighboring barrel cortex. Systemic treatment with L-DOPA, a dopamine precursorused to treat PD, was able to partially correct this abnormal spine turnover. As a confirmation of this aberrant rewiring of motor cortex circuit maybe caused by loss of dopamine.(3) The neural circuits were remodeled in the M1 in PD:With the injected dosage of MPTP increasing, the dopaminergic neurons were damaged gradually. We found that the spine elimination and formation and turnover were consistently and cumulatively increased, but only a modest decrease in spine density. By repeatedly imaging the same dendritic regions of the same mice, we found percentages of stable pre-existing spine was reduced and new-stay spine was increased in PD mouse. These data indicated that the original neural connections were aberrant selectively interruptted and the new connections were established specificaly through aberrant spine elimination and formation following loss of dopamine, leading to a disorder in neural connections and an abnormal rewiring of the neuronal circuitry in M1.(4) Synaptic mechanisms for the motor skill learning and memory deficits in PD:We trained mouse with motor skill learning task, repeatedly imaged the same dendritic regions during different learning stages, and analysised of spine elimination and formation and stabilization which were induced by learning task in M1. The results showed that in PD mouse model motor learning and memory were damaged in behaviorally, the learning induced spine elimination and formation were injured in neural circuits, the stabilization of learning-induced, newly formed spines were clearly impaired. So we speculated the synaptic mechanisms of the motor skill learning and memory deficits in PD were the abnormal rewiring of the neuronal circuitry following DA depletion.Taken together, we verified the abnormal rewiring of the neuronal circuitry in PD mice in M1 by repeatedly in vivo imaging. Finding the basic structural unit of neural signal transmission synapses marked increases in both elimination and formation. We also combined with behavioral experiment, preliminaryly elucidating the synaptic mechanisms for the motor skill learning and memory deficits seen in PD.