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

Hyperreflexia, spasticity, and a loss of skilled motor function are consequences of spinal cord injury (SCI). Multiple potential mechanisms underpinning hyperreflexia have been reported, including: aberrant proprioceptive afferent (PA) sprouting, which could enhance reflex signaling; reduced GABAergic inhibitory presynaptic regulation of 1A terminals (GABApre); and increased excitability produced by reduced motor neuron membrane-bound potassium-chloride co-transporter #2 (KCC2), which has only studied after SCI and bilateral CST lesion. Here we examine how selective CST injury allows for specific investigation of the different mechanisms to determine their contributions to hyperreflexia. Hoffmann (H)-reflex rate-dependent depression (RDD) of the forelimb and hindlimb 5 -digit abductor muscles was used to assess hyperreflexia. We compared RDD in naïve and unilateral-PTX animals at 7-dpi and 42-dpi, supplemented with additional timed tests to examine the time-course of hyperreflexia development. Immunohistochemistry was used to identify PA synapses (VGlut1) and GABApre (GABApre), motor neurons (ChAT), and KCC2. Following unilateral PTX, which eliminates the CST from one hemisphere, 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. 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.