Role of GluK1-containing kainate receptors in the development of cortico-striatal projections

Kainate receptors are ionotropic glutamate receptors, involved in modulation of synaptic transmission in developing and adult brain. Genetic disruption of all five kainate receptor subunits reduces cortico-striatal synaptic connectivity and leads to OCD-related pathological behavior. The aim of the project is to evaluate if the OCD-like pathology arises due to the deficit in the development of cortico-striatal projections due to the lack of the kainate receptor subunit 1 (GluK1). We characterized the expression of GluK1 during the development of the cortico-striatal circuitry using immunohistochemistry and assessed if GluK1-containing receptors regulate cortico-striatal synaptic transmission by the whole cell patch-clamp. We have shown that during the early postnatal development GluK1 subunit is expressed in cortical neurons, which innervate striatum. In developing, but not adult striatal medium spiny neurons (MSNs) pharmacological activation of GluK1 increases the frequency of spontaneous glutamatergic synaptic currents. Interestingly, GluK1 agonist does not affect the frequency of miniature synaptic events, frequency of spontaneous events in slices without cortex and short-term synaptic plasticity in developing MSNs. Preliminary data indicate that activation of GluK1 receptors may increase the excitability of neonatal layer V pyramidal cells. We can conclude that GluK1-containing receptors, expressed by layer V pyramidal cells, increase the efficiency of cortico-striatal synaptic contacts during the restricted period of brain development. We created grik1 conditional local cortical knockouts to further evaluate the role of GluK1 in development of cortico-striatal connectivity and possible occurrence of OCD-like behavior in adult animals.