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bioRxiv · 10.1101/2025.02.21.639555

Hyperreflexia after corticospinal tract lesion reflects 1A afferent circuit changes not increased KCC2 hyperexcitability

Bethea, T.·Adegbenro, T.·Martin, J. H.
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Abstract

Hyperreflexia is a consequence of spinal cord injury (SCI) and motor system lesions in the brain Two major mechanisms underpinning hyperreflexia have been reported: proprioceptive afferent (PA) circuit changes produced by 1A fiber sprouting, which could enhance reflex signaling, together with reduced GABAergic inhibitory presynaptic regulation (GABApre); and increased intrinsic motor neuron excitability, for example, produced by reduced motor neuron membrane-bound potassium-chloride co-transporter2 (KCC2). Here we examine how selective unilateral CST injury in the medullary pyramid (PTX), which eliminates the CST from one hemisphere, allows for specific investigation of the different mechanisms to determine their contributions to hyperreflexia. We used rate-dependent depression (RDD) of the Hoffmann (H)-reflex for the forelimb and hindlimb 5th-digit abductor muscles to assess hyperreflexia on both the contra-and ipsilesional sides. We compared RDD in naive and unilateral-PTX rats at 7-dpi and 42-dpi, supplemented with additional timepoints to examine hyperreflexia development. Immunohistochemistry was used to identify PA synapses (VGlut1), GABA presynaptic boutons (GABApre), motor neurons (ChAT), and to measure KCC2. Following unilateral PTX, we observed significant hyperreflexia in the contralesional forelimb only. Membrane-bound KCC2 was unchanged in contralesional cervical motor neurons. Whereas both cervical and lumbar motor neurons showed increased PA sprouting contralesionally, there was a concomitant increase in GABApre terminals for the lumbar not cervical cord, which associated with a normal hindlimb H-reflex. Our findings show that KCC2 is disassociated from hyperreflexia in the uniPTX model. Instead, forelimb hyperreflexia can be explained by cervical motor neuron PA sprouting and an uncompensated GABApre regulation.

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Bethea, T., Adegbenro, T., Martin, J. H.. 2025-02-23. Hyperreflexia after corticospinal tract lesion reflects 1A afferent circuit changes not increased KCC2 hyperexcitability. https://doi.org/10.1101/2025.02.21.639555

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