Kainate receptor regulation of synaptic inhibition in the hippocampus

Kainate receptors (KARs) are glutamate-type receptors that mediate both canonical ionotropic currents and non-canonical metabotropic signalling. While KARs are expressed widely throughout the brain, synaptic KAR currents have only been recorded at a limited set of synapses, and the KAR currents that have been recorded are relatively small and slow, which has led to the question, what is the functional significance of KARs? While the KAR current itself is relatively modest, its impact on inhibition in the hippocampus can be profound. In the CA1 region of the hippocampus, presynaptic KAR activation bidirectionally regulates γ-aminobutyric acid (GABA) release in a manner that depends on the glutamate concentration; lower levels of glutamate facilitate GABA release via an ionotropic pathway, while higher levels of glutamate depress GABA release via a metabotropic pathway. Postsynaptic interneuron KAR activation increases spike frequency through an ionotropic current, which in turn can strengthen inhibition. In the CA3 region, postsynaptic KAR activation in pyramidal neurons also strengthens inhibition, but in this case through a metabotropic pathway which regulates the neuronal chloride gradient and hyperpolarizes the reversal potential for GABA (E_GABA ). Taken together, the evidence for KAR-mediated regulation of the strength of inhibition via pre- and postsynaptic mechanisms provides compelling evidence that KARs are ideally positioned to regulate excitation-inhibition balance - through sensing the excitatory tone and concomitantly tuning the strength of inhibition.