Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons.
The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.
['Chu|Hong-Yuan|HY|', 'McIver|Eileen L|EL|', 'Kovaleski|Ryan F|RF|', 'Atherton|Jeremy F|JF|', 'Bevan|Mark D|MD|']
D000818:Animals D001522:Behavior, Animal D002540:Cerebral Cortex D003342:Corpus Striatum D059290:Dopaminergic Neurons D055785:Gene Knockdown Techniques D005917:Globus Pallidus D008124:Locomotion D017774:Long-Term Potentiation D008297:Male D051379:Mice D008822:Mice, Transgenic D009433:Neural Inhibition D009434:Neural Pathways D016627:Oxidopamine D010300:Parkinson Disease D016194:Receptors, N-Methyl-D-Aspartate D020531:Subthalamic Nucleus D009435:Synaptic Transmission
cortex subthalamic nucleus synapse NMDA Parkinson’s disease basal ganglia globus pallidus glutamate plasticity