Presynaptic AMPA and kainate receptors increase the size of GABAergic terminals and enhance GABA release

Abstract

SUMMARYIn the developing cerebellum, NMDA receptors promote the maturation of axonal terminals of inhibitory interneurons. We compared the effects of AMPA/kainate receptor agonists in cultured cerebellar cells from GAD65-eGFP mice. Both AMPA and kainate augmented granule cell survival without affecting interneurons. The action of kainate was blocked by an AMPA but not by a NMDA receptor antagonist, suggesting AMPA receptor involvement. AMPA and kainate increased the size of the GABAergic terminals and the action of kainate was insensitive to NMDA blockers. Whole cell recordings in granule neurons revealed that chronic treatments for 5 days with kainate as well as NMDA decreased AMPA receptors expression while interneuronal kainate receptors were depressed by kainate treatment. Acute kainate applications increased mIPSCs frequency in both granule neurons and interneurons and this effect was only partially blocked by an AMPA receptor antagonist. In contrast to what was reported for NMDA, chronic treatments with kainate induced a significant decrease of the basal mIPSCs frequency but increased the acute action of kainate on mIPSCs. Direct recordings from presynaptic GABAergic terminals suggest that AMPA and kainate receptors are present in developing GABAergic terminals and their activation affect the size of GABAergic terminals and spontaneous GABA release.

Calcium‐permeable presynaptic AMPA receptors in cerebellar molecular layer interneurones

“…Our Ca 2+ imaging experiments with (PN 19–21) animals confirm the hypothesis of a developmental switch (Bureau & Mulle, 1998) that could correspond to a displacement of AMPARs from the axonal to the somato‐dendritic compartment. Interestingly, it has been reported that presynaptic ionotropic glutamate receptors promote the maturation of GABAergic basket/stellate interneurones and increase the size of their axonal terminals thus enhancing GABA release (Fiszman et al 2005, 2007). It seems likely that activation of presynaptic Ca 2+ ‐permeable AMPARs represents an important step in the developing cerebellum.…”

“…Moreover, activation of presynaptic NMDARs promotes the spontaneous release of Ca 2+ from presynaptic ryanodine‐sensitive Ca 2+ stores (RyCSs) thus enhancing the release of GABA at the MLI‐Purkinje cell synapse (Duguid & Smart, 2004) and activation of extrasynaptic NMDARs induces a switch in synaptic receptor subtypes under PKC control (Sun & Liu, 2007). Finally, it has been demonstrated in cerebellar cultures that AMPARs are present in developing GABAergic terminals and their activation affects the size of GABAergic terminals and spontaneous GABA release (Fiszman et al 2007).…”

“…receptor subtypes under PKC control (Sun & Liu, 2007). Finally, it has been demonstrated in cerebellar cultures that AMPARs are present in developing GABAergic terminals and their activation affects the size of GABAergic terminals and spontaneous GABA release (Fiszman et al 2007).…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…AMPA Receptor Function in Presynaptic Signaling. AMPA receptors are present in the presynaptic compartments of neurons in hippocampus, striatum, and spinal cord (Lu et al, 2002;Schenk et al, 2003;Fujiyama et al, 2004;Fiszman et al, 2007;Haglerod et al, 2017) and can potentially influence synaptic function by multiple means, including as autoreceptors that respond to glutamate in the synaptic cleft or as receptors on nearby terminals to impact vesicular release properties in response to glutamate that has diffused from a different synapse. Whereas the autoreceptor paradigm represents a conventional form of presynaptic regulation, the second form allows AMPA receptors to participate in intersynaptic communication.…”

Presynaptic AMPA Receptors in Health and Disease

“…Whole-cell recordings confirmed the functional relevance of these morphological changes. Indeed, kainate increased the spontaneous synaptic release from GABAergic interneurons in cerebellar cultures [ 38 ].…”