Glutamate, cell death, and hats off to Carl Cotman.

摘要: honoring Carl Cotman, as Icount myself amongst the many neuroscientists who havebenefited from Carl’s long and distinguished career to date.My own debt is clear. Twenty years ago, emergingfrom sequestration in neurology clinical training, Ijoined faculty at Stanford University began setup my laboratory. As a graduate student, I had workedpreviously on GABAergic neurotransmission benzo-diazepines, but during training this field hadmoved on. So decided switch over synapticsignaling mediated by GABA’s excitatory aminoacid partner, glutamate: equally widespread, accessible tosimilar electrophysiological approaches, and, time,attractively enigmatic. Why was postsynaptic res-ponse applied glutamate so complex, times evensuggestive of conductance closure, rather than theexpected gating? And, it possible thata ubiquitous signaling molecule could become killingagent under certain pathological conditions, destroyingcentral neurons process John Olney called “excito-toxicity.” The former puzzle quickly solved whenthe voltage-dependent block NMDA receptor–gatedchannels magnesium identified (1,2). latterpuzzle yielded more slowly, extensive studiesin provided boost guidance overmany years.He pioneer studying central glutamater-gic (3,4) phenomenon ex-citotoxicity (5). His work supporting idea aglutamine–glutamate cycle (6) helped highlight theimportance astrocytes regulating transmitter gluta-mate synthesis set stage for appreciation anequally prominent role pathogenesisof excitotoxicity after acute insults. Under depolarizingconditions, later compounded acid stress energyfailure, fail clear extracellular glutamate;rather, they export via reverse transport thuscontribute toxic buildup inthe ischemic brain (7).Carl’s lab also produced beautiful maps thecentral distribution major receptor fami-lies, providing insights into complexity spa-tial diversity glutamatergic neurotransmission(8). significance these regional differences inglutamate family expression still remainslargely be elucidated, point possi-bility that selective antagonists or potentiators mightgain useful leverage against disease targets. In earlydays, antiexcitotoxic treatments seemed implausiblepractical treatments: how one hope alarge fraction receptors without disrupt-ing vital functions? A path forward toappear when subtype recep-tors identified bearing responsibilityfor neurotoxicity (9), consequenceof high calcium permeability. But antagonistshave been disappointing stroke trials. Is theapproach finished?Some have suggested mightstill find application treatment if carriedto higher level selectivity. particular, subsubtypeselective targeting NR2B receptorsmight achieve better therapeutic index pan NMDAreceptor antagonists, preferentially attenuating excitotoxicdamage forebrain with reduced motor impairment(10) perhaps tendency promote apopto-sis because an excessive receptor–mediated influx (11). Partial, use-dependentantagonism may another route improving ther-apeutic neuroprotection; low-affinity, use-dependent antagonist memantine has recentlybeen demonstrated reduce progression ofAlzheimer’s (12). And AMPA/kainate antagonistsmay their neuroprotective uses, example,in protecting CA1 transient global ischemia.These selectively vulnerable prominently expressCa