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

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