Gluk4-containing kainate receptors regulate synaptic communication in the motor cortex and reduce axon degeneration in adult mice

Abstract

Glutamate-gated kainate receptors comprising the Gluk4 subunit (encoded by Grik4) are highly expressed by neurons in the central nervous system. We report that Grik4 mRNA is widely expressed by neurons in the adult mouse motor cortex, where GluK4-containing kainate receptors account for ~60% of the kainate evoked current in layer V pyramidal neurons. To elucidate their role in motor circuit regulation, we analyzed the behavior of mice that lacked the pore forming domain of the GluK4 subunit (Grik4-/- mice). Grik4-/- mice were hyperactive, had an abnormal gait, and impaired motor coordination. At postnatal day (P)60, layer V pyramidal neurons received fewer miniature excitatory post synaptic currents, had a reduced density of thin spines on their basal dendrites, and a reduced density of VGlut1 puncta at the soma, consistent with neurons receiving fewer excitatory synaptic connections. Grik4-/- mice also lost ~44% of their callosal axons between P60 and P180 and the amplitude of the callosal compound action potential was reduced by ~25-30%. RNA sequencing data support the capacity for Grik4 to modulate synaptic and neuroprotective signaling pathways.