AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

Abstract

Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) ␥-2 (or stargazin) and the related TARP ␥-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocampal enriched ␥-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. ␥-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking ␥-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.excitotoxicity ͉ epilepsy ͉ PSD-95 ͉ synapse T he ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors are selective cation channels and mediate most of the postsynaptic depolarization that induces neuronal firing. Dynamic trafficking of neuronal AMPA receptor proteins participates in the plasticity of synaptic transmission that underlies aspects of learning and memory. AMPA receptor channels comprise heterotetramers of subunits GluR1-4, and each subunit can be alternatively spliced as either a flip or flop form (1, 2). The distinct expression of these AMPA receptor subunits and alternatively spliced isoforms in discrete neuronal populations helps determine differential AMPA receptor function and synaptic plasticity throughout the brain (3-7).Neuronal AMPA receptors also contain transmembrane AMPA receptor-regulatory protein (TARP) auxiliary subunits (8). The TARP family comprises five isoforms: ␥-2 (or stargazin), ␥-3, ␥-4, ␥-7, and ␥-8, which are predominantly expressed in adult cerebellum, adult cerebral cortex, early developmental brain, cerebellar Purkinje cells, and adult hippocampus, respectively (9, 10). Stargazer mice, which show absence epilepsy and cerebellar ataxia, have a genetic mutation in stargazin, the prototypical TARP (11). Physiological studies have shown that cerebellar granule cells from stargazer mice selectively lack functional AMPA receptors (12). Biochemical and cell biological studies have shown that stargazin binds to AMPA receptors and traffics the receptors to the neuronal cell surface (13,14). Interaction of stargazin with the postsynaptic density-95 and related proteins (15) mediates synaptic clustering of AMPA receptors (16,17). Stargazin also cooperates with postsynaptic density-95 to control synaptic plasticity (18)(19)(20). In addition to trafficking AMPA receptors, stargazin modulates th...

Decreased kainate receptors in the hippocampus of apolipoprotein D knockout mice

“…Thus, our data would seem to support the hypotheses that ApoD may have a role in maintaining the glutamatergic function in the mammalian CNS. This hypothesis is consistent with previous data showing that exogenous ApoD can help protect against the neurotoxic effects of kainic acid (He et al, 2009), some of which are mediated by KAR (Garthwaite and Wilkin, 1982) and AMPAR (Tomita et al, 2007). It has been previously shown that ApoD -/-mice have complex,…”

CRMP2 Tethers Kainate Receptor Activity to Cytoskeleton Dynamics during Neuronal Maturation

“…No differences were found in KA-treated cultures compared with untreated cultures (data not shown), indicating that KA was not toxic under our experimental conditions. This is consistent with the suggestion that KAinduced activation of AMPARs, rather than KARs, is mostly responsible for KA excitotoxicity (Tomita et al, 2007). We also measured KA-induced currents in the three stages of maturation and found that KA (30 M; Ϫ60 mV of holding potential) induced ionotropic responses in ϳ70 -75% of cells studied with amplitudes that were not significantly different among the three different maturation stages.…”

Effects of Quercetin on Human α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor-Mediated Ion Currents

“…4,5,[25][26][27] Quercetin attenuates in vitro and in vivo excitotoxin-mediated insults. 15,16,39,40) The present findings on the inhibitory effects of quercetin on AMPA receptor channel activity with voltage-dependent manner might be one of the main contributors to neuroprotection against AMPA receptor-related neurotoxicity.…”

“…4,5,10,[25][26][27] Agents that regulate ionotropic glutamate receptor channel currents are studied for the development of neuroprotective agents through natural sources or synthesis. As a natural source, quercetin is one of several flavonoids and is a well-known anti-oxidant.…”