Kainate Receptors Modulating Glutamate Release in the Cerebellum

Abstract

Glutamate receptors of the kainate type (Kainate receptors, KARs), are mediators of ionotropic postsynaptic synaptic transmission, as well as presynaptic modulators of neurotransmitter release where they show both ionotropic and metabotropic actions regulating glutamate and γ-aminobutiric acid (GABA) release. The mechanisms underlying these modulatory roles are starting to be understood at some brain regions. Here we review the KARs roles and mechanisms involved in the modulation of glutamate release in the cerebellum at parallel fibers (PF)-Purkinje Cells (PuC) synapses. KARs activation mediate a biphasic effect on glutamate release at this synapse, with low kainate (KA) concentrations mediating a facilitation of glutamate release and higher KA concentrations mediating a depression of glutamate release. KA-mediated facilitation is prevented by antagonizing KARs, by inhibition of PKA or stimulation of adenylyl cyclase (AC), by blocking Ca 2+ permeant KARs, by depleting intracellular Ca 2+ stores and by blocking calmodulin. Thus, at cerebellar parallel fiber-Purkinje cell synapses, presynaptic KARs mediate glutamate release facilitation through Ca 2+-calmodulin dependent activation of adenylyl cyclase/cAMP/protein kinase A signaling. KAR-mediated depression of glutamate release involves the AC/cAMP/PKA pathway as for facilitation but not Ca 2+-calmodulin, being in this case AC activated by a Gi/o protein to mediate a depression of glutamate release.

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum

“…The normal development of the cerebellum depends on exact coordinated actions carried out by a large number of glutamate receptors. Some glutamate receptors, such as NMDA receptors, have been linked to climbing fiber synaptic pruning and granule cell migration [ 82 , 83 , 84 ]. The function of KARs during cerebellar development is poorly understood.…”

“…However, the predominance of KAR subunit expression in the development of immature cerebellar granule cells raises the possibility that KARs play a part in synaptic transmission and maturation. KAR subunits may present varying levels of expression and different functions in the developing cerebellum [ 66 , 67 , 82 ]. Preliminary studies earlier on the KAR expression profile indicates that once an adult stage is reached, the expression of KARs containing GluK1 subunit is decreased in the granule cell layer, whereas the expression of GluK2 and GluK5 does not change [ 67 ].…”

“…A recent case report has shown that missense variants of the GRIK2 gene, which encodes GluK2 protein, give rise to neurodevelopmental disorder of diverse phenotype including cerebellar atrophy at an individual of about three years of age, suggesting a critical importance of KAR function during early development of the cerebellum [ 86 ]. Indeed, the predominance of GluK2 and GluK5 throughout the developmental period suggests that KAR subunits may be essential for cerebellar development [ 82 ]. Together with the distribution of KARs in the different cell types of the cerebellum as discussed in the previous paragraph, all these results imply that KARs play an important role in cerebellar development.…”

“…This finding was initially reported in a study of the hippocampus, and this effect has been further discovered in the cortex, the amygdala, and the thalamus [ 97 , 98 , 99 ]. Electrophysiological recordings demonstrated that exogenous KAR agonists regulate transmitter release at both excitatory and inhibitory synapses in a biphasic fashion dependent upon synapse type and agonist concentration, whereas endogenous activation by released glutamate at synapses is predominantly facilitatory [ 11 , 48 , 49 , 82 , 100 ]. In agreement with what has been found in other brain regions, the bidirectional modulation of transmitter release has been recently found in the cerebellum.…”