Developing roles for kainate receptors in the cerebellum.

Nine years on from the cloning of a cDNA encoding the first member of the kainate receptor gene family, a consensus has yet to be reached regarding the physiological function of this group of ionotropic glutamate receptors. In contrast, their better-known channel siblings, AMPA and NMDA receptors, are known to mediate excitatory synaptic transmission and play key roles in synaptic plasticity, and have been implicated in the pathology of excitotoxicity. In the face of a wealth of information concerning the pharmacological and physiological properties of recombinant kainate receptors, why do they remain the most poorly defined glutamate receptor system in the brain? The nature of the problem has been primarily threefold. First, neuronal currents arising from kainate receptors have been difficult to distinguish from those gated by AMPA-type glutamate receptors (and neurons seem typically to express populations of both receptor types). Second, kainate receptors appear to be expressed at significantly lower levels than AMPA receptors. Third, the kinetic properties of some native kainate receptors (in particular, the postsynaptic kainate receptor current in hippocampal CA3 pyramidal neurons) have not corresponded to those observed in studies of recombinant receptors (reviewed by Chittajallu et al. 1999). Progress has been made towards addressing the most problematic of these issues with the development of relatively selective agonists and antagonists, which has resulted in a minor flood of reports that have characterized synaptic kainate receptor currents. It can be anticipated that as these pharmacological and genetic tools become more widely available, the once difficult task of finding and characterizing kainate receptors will become routine in many neuronal populations. However, the ability to detect and describe neuronal kainate receptors has not led to a clear understanding of their role in brain function. Much of the recent interest in kainate receptors has focused on their involvement in synaptic transmission, whether on the postsynaptic or presynaptic side of the terminal. Alternatively, a role in neuronal development was suggested by early reports following in situ hybridization mapping of the expression of kainate receptor mRNAs in the rat brain at a variety of developmental time periods (Bahn et al. 1994). GluR5 mRNA, in particular, showed a peak postnatal window of expression in the somatosensory cortex that corresponded to cortical synaptogenesis. Furthermore, GluR5 and GluR6 mRNAs are subject to tightly regulated RNA editing, which occurs at very low levels in embryonic brain and increases to approximately 50 % (GluR5) and 80 % (GluR6) of the mRNA transcripts within the first few days after birth in most regions of rat brain (see, for example, Bernard et al. 1999). Editing of the Q/R (glutamine/arginine) site in GluR5 and GluR6 mRNAs alters a critical residue in the resultant protein, producing subunits which combine to form receptors with much lower calcium permeabilities and single-channel conductances (reviewed by Dingledine et al. 1999). In principle, one could draw conclusions about the Q/R site editing state, and thus the calcium permeability, of kainate receptors in neurons based on comparison of their single-channel conductances with those reported for the recombinant receptors. A report by Smith et al. (1999) in this issue of The Journal of Physiology does just that and thereby infers the presence of calcium-permeable kainate receptors in a population of immature granule cells in acute slices of mouse cerebellum. This result, in combination with their observation that the expression of kainate receptor currents predominates over AMPA receptor currents in pre-migratory neurons in the external granule layer (EGL), provides further suggestive evidence that kainate receptors may play a unique role in development. Smith et al. (1999) focused their efforts on providing functional support for earlier biochemical data suggesting that kainate receptors were expressed in the EGL of the mouse cerebellum (Ripellino et al. 1998). The EGL contains undifferentiated granule cells that eventually migrate through the molecular and Purkinje cell layers during cerebellar development. An earlier report from the same laboratory found that AMPA receptor immunoreactivity was undetectable in the EGL, whereas staining for GluR6/7 subunits was present in the EGL at birth (Ripellino et al. 1998). This result provided evidence for marked disparity in the expression of AMPA and kainate receptors in developing cerebellar granule cells, and naturally begged the question of whether the kainate receptor immunoreactivity observed in the EGL correlated with expression of functional receptors. By blocking AMPA receptors with GYKI 53655 and potentiating kainate receptors with concanavalin A, Smith et al. (1999) have demonstrated that EGL granule neurons do indeed contain functional kainate receptors (Figs 1 and 2 in Smith et al. 1999). In contrast to most neuronal cell types, including granule cells in the internal granule layer (IGL), kainate receptor currents in the EGL granule cells were of larger amplitude than those elicited by activation of AMPA receptors. Furthermore, noise analysis and direct resolution of kainate receptor single-channel currents in the EGL neurons revealed the presence of high-conductance (∼4 pS) channels, which is similar to the single-channel conductances of calcium-permeable recombinant kainate receptors (reviewed in Dingledine et al. 1999). Kainate receptor currents in granule cells in the IGL had a lower single-channel conductance (1.8 pS), suggesting that they were predominantly composed of calcium-impermeable receptor subunits. These results are intriguing because they suggest that kainate receptors may have a special role in the development or proliferation of cerebellar granule cells. Furthermore, they serve as a useful reminder of earlier speculation (Bahn et al. 1994) that kainate receptors, as a result of their permeability to calcium, may be critical components of the process of development rather than simply bit players at excitatory synapses. As pointed out by Smith et al. (1999) their results do not answer the fundamental question of the function of granule cell kainate receptors and the utility of tight developmental regulation of receptor composition and channel properties. However, Smith et al. (1999) provide a solid base from which to explore a potentially novel developmental role for cerebellar kainate receptors.