Abstract
Destabilization of faciliatory and inhibitory circuits is an important feature of corticomotor pathology in amyotrophic lateral sclerosis (ALS). While GABAergic inputs to upper motor neurons are reduced in models of the disease, less understood is the involvement of peptidergic inputs to upper motor neurons in ALS. The neuropeptide Y (NPY) system has been shown to confer neuroprotection against numerous pathogenic mechanisms implicated in ALS. However, little is known about how the NPY system functions in the motor system. Herein, we investigate post-synaptic NPY signaling on upper motor neurons in the rodent and human motor cortex, and on cortical neuron populations in vitro. Using immunohistochemistry, we show the increased density of NPY-Y1 receptors on the soma of SMI32-positive upper motor neurons in post-mortem ALS cases and SOD1G93A excitatory cortical neurons in vitro. Analysis of receptor density on Thy1-YFP-H-positive upper motor neurons in wild-type and SOD1G93A mouse tissue revealed that the distribution of NPY-Y1 receptors was changed on the apical processes at early-symptomatic and late-symptomatic disease stages. Together, our data demonstrate the differential density of NPY-Y1 receptors on upper motor neurons in a familial model of ALS and in ALS cases, indicating a novel pathway that may be targeted to modulate upper motor neuron activity.
Highlights
Published: 23 July 2021The motor cortex is a region of the frontal lobe responsible for learning and planning of complex motor sequences and relay of behavioral and environmental cues to modify movements elicited by downstream motor pathways
This includes the dense perisomatic innervation received by upper motor neurons from within layer 5 of the motor cortex, which strongly influences cell output [47], and the axo-dendritic innervation received from layer 2/3 cells onto upper motor neuron apical dendrites, which influences temporal summation [48,49,50]
To understand whether increased neuropeptide Y (NPY)-Y1 receptor density persists throughout disease, of fluctuates with key stages of disease, we investigated layer 5 upper motor neurons in the motor cortex of the SOD1G93A mouse at an early-symptomatic (8 week) and latesymptomatic (20 week) time point
Summary
Published: 23 July 2021The motor cortex is a region of the frontal lobe responsible for learning and planning of complex motor sequences and relay of behavioral and environmental cues to modify movements elicited by downstream motor pathways. The E/I ratio is shaped by a heterogeneous network of different cell types, receptors and signaling mechanisms [1], and changes to any one of these components can trigger significant effects on the overall function and activity of the corticomotor system. In the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), the destabilization of faciliatory and inhibitory signaling represents an important aspect of corticomotor pathology. E/I state of brain networks contribute to cortical hyperexcitability in the motor cortex of patients, preceding lower motor neuron loss, and coinciding with the emergence of motor symptoms [2,3,4]. There is increased interest in determining the exact mechanisms of cortical hyperexcitability in ALS, as recent studies indicate that it may be a critical determinant of disease progression and a therapeutic target capable of delaying
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