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

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 analysed the behaviour 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 signalling pathways.