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Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons.

ABSTRACT: 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.

SUBMITTER: Chu HY

PROVIDER: S-EPMC5679443 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons.

Chu Hong-Yuan HY McIver Eileen L EL Kovaleski Ryan F RF Atherton Jeremy F JF Bevan Mark D MD

Neuron 20170901 6

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 c ...[more]

PMID: 28910619

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Project description:Key pointsMotor units, comprising a motor neuron and the muscle fibre it innervates, are activated in an orderly fashion to provide varying amounts of force. A unilateral C2 spinal hemisection (C2SH) disrupts predominant excitatory input from medulla, causing cessation of inspiratory-related diaphragm muscle activity, whereas higher force, non-ventilatory diaphragm activity persists. In this study, we show a disproportionately larger loss of excitatory glutamatergic innervation to small phrenic motor neurons (PhMNs) following C2SH, as compared with large PhMNs ipsilateral to injury. Our data suggest that there is a dichotomy in the distribution of inspiratory-related descending excitatory glutamatergic input to small vs. large PhMNs that reflects their differential recruitment.AbstractExcitatory glutamatergic input mediating inspiratory drive to phrenic motor neurons (PhMNs) emanates primarily from the ipsilateral ventrolateral medulla. Unilateral C2 hemisection (C2SH) disrupts this excitatory input, resulting in cessation of inspiratory-related diaphragm muscle (DIAm) activity. In contrast, after C2SH, higher force, non-ventilatory DIAm activity persists. Inspiratory behaviours require recruitment of only smaller PhMNs, whereas with more forceful expulsive/straining behaviours, larger PhMNs are recruited. Accordingly, we hypothesize that C2SH primarily disrupts glutamatergic synaptic inputs to smaller PhMNs, whereas glutamatergic synaptic inputs to larger PhMNs are preserved. We examined changes in glutamatergic presynaptic input onto retrogradely labelled PhMNs using immunohistochemistry for VGLUT1 and VGLUT2. We found that 7 days after C2SH there was an ∼60% reduction in glutamatergic inputs to smaller PhMNs compared with an ∼35% reduction at larger PhMNs. These results are consistent with a more pronounced impact of C2SH on inspiratory behaviours of the DIAm, and the preservation of higher force behaviours after C2SH. These results indicate that the source of glutamatergic synaptic input to PhMNs varies depending on motor neuron size and reflects different functional control - perhaps separate central pattern generator and premotor circuits. For smaller PhMNs, the central pattern generator for inspiration is located in the pre-Bötzinger complex and premotor neurons in the ventrolateral medulla, sending predominantly ipsilateral projections via the dorsolateral funiculus. C2SH disrupts this glutamatergic input. For larger PhMNs, a large proportion of excitatory inputs appear to exist below the C2 level or from contralateral regions of the brainstem and spinal cord.

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Dataset Information

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons.

Publications

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons.

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