overactivation of post - synaptic receptors for glutamate places a metabolic stress upon neurons which can contribute to neuronal injury in a wide range of conditions . the evidence for a contribution of glutamate receptor overactivation ( termed  excitotoxicity  ) is strongest in conditions like ischemia , prolonged seizures , and trauma , in which there is rapid release and extracellular accumulation of glutamate . however , there is also compelling evidence for important excitotoxic contributions to injury in neurodegenerative conditions including amyotrophic lateral sclerosis ( als ) . glutamate acts at a number of receptors comprising both ligand gated ion channels ( ionotropic receptors ) and g - protein linked ( metabotropic ) receptors . three families of ionotropic glutamate receptors ( nmda , ampa , and kainate receptors ) have been characterized both pharmacologically and by the identification and cloning of their subunit genes . early studies of excitotoxic mechanisms focused on possible contributions of nmda receptors , which unlike most ampa , and kainate receptors ( collectively referred to as ampa / kainate receptors ) , are highly permeable to ca ions , and brief activation of which could potently trigger delayed injury to cultured neurons . however , despite clear contributions of these channels in some models of acute neurodegeneration , nmda blockers have to date failed to show impressive efficacy in therapeutic trials . furthermore , in some studies ampa / kainate receptor blockade has shown greater efficacy against ischemic injury than nmda receptor antagonism ( buchan et al . , 1993 ) . another early clue to contributions of ampa / kainite in neurodegeneration derives from studies of syndromes in humans or primates linked to the consumption of environmental toxins , beta - n - methylamino - l - alanine ( bmaa ) , beta - n - oxalylamino - l - alanine ( boaa ) , and domoic acid ( spencer et al . , 1986 , 1987 ; teitelbaum et al . , boaa and domoic acid , the respective causes of lathyrism and a form of shellfish poisoning , are both well established ampa / kainate receptor agonists . bmaa , an unusual cyanobacterial toxin suspected of contributing to forms of human neurodegenerative disease , can induce selective injury to vulnerable subpopulations of neurons , including motor neurons ( mn , which degenerate in als ) , via activation of ampa / kainate receptors ( weiss et al . , 1989 ; weiss and choi , 1991 ; rao et al . , 2006 ) . whereas most ampa / kainate type glutamate channels are ca impermeable , subsets of these channels , which are expressed in characteristic temporal and spatial patterns on discrete populations of neurons , are ca - permeable , and it is the activation of these channels that likely mediates most of the neurodegeneration attributable to ampa / kainate receptor activation . this review focuses specifically on ca - permeable ampa ( ca - ampa ) channels and clues that have accumulated over the past two decades to their roles in both acute and chronic neurodegenerative conditions . ampa channels are the most prevalent glutamate channels in the mammalian central nervous system , and mediate most routine excitatory neurotransmission . they are tetramers comprised of combinations of four subunits  glua ( previously referred to as glur ) 1 , 2 , 3 , or 4 . the presence of one or more glua2 subunits in a heteromeric channel prevents ca permeability . the ability of glua2 subunits to block ca permeability is dependent upon the presence of a positively charged arginine residue at a critical site in the channel lining region of the peptide ( the  q / r site  ) ; the other ampa subunits ( glur1 , 3 , and 4 ) all have a neutral glutamine at the homologous site . interestingly , the genomic dna encodes a neutral glutamine residue at this site in all four subunits , and the arginine codon is post - transcriptionally inserted into the glua2 mrna transcript via rna editing by the enzyme adar2 ( higuchi et al . , 2000 ) . after translation , the subunits are assembled in the er . likely indicative of the critical importance of these channels to normal physiological function , channel assembly , and membrane insertion are both sensitive to the editing state of glua2 ( greger et al . it has further become apparent that pathological upregulation of these channels in disease states can occur via several mechanisms , including downregulation of glua2 mrna transcription , defective editing of the glua2 pre - mrna , and aberrant internalization of glua2 containing ( and ca impermeable ) channels and insertion of glua2 lacking channels . the presence of ca - ampa channels is neither uniform nor constant , but varies with cell type and developmental stage . whereas most adult neurons possess relatively few of these channels , discrete populations of neurons , most prominently many gabaergic inhibitory interneurons , possess large numbers of ca - ampa channels ( jonas et al . , 1994 ; yin et al . , 1994a ; leranth et al . , 1996 ) . however , numbers of ca - ampa channels on pyramidal neurons change with developmental stage , and are present in markedly increased numbers in both rats and humans in early postnatal periods ( kumar et al . , 2002 ; talos et al . , 2006a , b ; brill and huguenard , 2008 ) . as mentioned above , relatively brief but strong activation of highly ca permeable nmda channels is sufficient to trigger degeneration of cultured neurons . a large number of studies have highlighted mechanisms through which such neuronal ca loading can induce injury , which may vary depending upon the intensity of the ca load . with strong loading , ca is taken up into mitochondria and can disrupt their function , causing release of damaging reactive oxygen species ( ros ; dugan et al . , 1995 ; reynolds and hastings , 1995 ) . in addition , ca loading can induce ros generation through other mechanisms , including the activation of nitric oxide synthetase ( nos ) , with resultant nitric oxide production , and the activation of nadph - oxidase , with resultant superoxide production ( dawson et al . these ros may induce dna damage , causing activation of the enzyme , parp , which can injure neurons via nad+ depletion , resulting in glycolytic block , depletion of atp , and induction of apoptotic signaling via release of aif from mitochondria ( hong et al . it appears likely that many of these same downstream mechanisms may apply to injury caused by strong activation of ca - ampa channels ( carriedo et al . , 1998 ) . a key question thus concerns differences between nmda and ca - ampa dependent injury , possibly accounting for the apparent greater contributions of ca - ampa channels in some conditions . one difference is that nmda channels are subject to a voltage dependent block of their pores by extracellular mg ions , such that there is relatively little ion flux through these channels in the absence of significant post - synaptic depolarization . this voltage dependence allows nmda channels to detect temporally and spatially convergent post - synaptic inputs and is thus important to their roles in activity dependent synaptic plasticity . in contrast , ca - ampa channels are not blocked by extracellular cations ( but are subject to voltage dependent block by intracellular polyamines , resulting in inwardly rectifying currents ) , and thus freely permit ca entry with any level of receptor activation . secondly , whereas the expression of nmda channels is relatively static , ampa channels are strongly regulated in response to physiological and pathological signals , and numbers of ca - ampa channels may increase sharply in certain stress conditions and disease states ( as discussed further below ) . thus , the increase in numbers of these channels in already stressed neurons adds an additional metabolic burden that may impair their ability to restore homeostasis and survive . a likely third factor in their propensity to contribute to injury concerns their permeability to other divalent cations . zn is present in pre - synaptic vesicles of many ( but not all ) forebrain excitatory pathways , and appears to be co - released with glutamate upon pre - synaptic activation ( assaf and chung , 1984 ; howell et al . , 1984 ; qian and noebels , 2005 ) . although the physiological significance of pre - synaptic zn release is uncertain , it can effectively block nmda channels , limiting their ion flux in response to intense pre - synaptic activation ( paoletti et al . , 2009 ) . in contrast , zn readily permeates ca - ampa channels ( jia et al . , 2002 ) , and its entry through these channels can clearly injure cultured neurons and likely contributes to injury in conditions like ischemia ( yin and weiss , 1995 ; sensi et al . , 1999 ; yin et al . , 2002 ; intracellular zn can trigger neurodegeneration via a number of mechanisms , including some previously attributed to ca , including the induction of mitochondrial dysfunction , which it appears to do with considerably greater potency than ca ( sensi et al . as mentioned above , some early studies found ampa / kainate blockers to provide greater protection than nmda blockers against ischemic neurodegeneration , and it is likely that much of this protection reflects blockade of ca - ampa channels . studies to date have suggested that ca - ampa channels may contribute to different forms of ischemic injury in a number of ways . the immature brain is particularly susceptible to ischemia , and pre - term , or perinatal hypoxia ischemia of both white and gray matter is a major cause of early life morbidity , for instance as an antecedent of cerebral palsy . a number of studies have indicated that periods of high ischemic susceptibility correspond to developmental periods of increased ca - ampa channel numbers , suggesting that the presence of these channels contributes to the ischemic susceptibility ( talos et al . transient global ischemia ( tgi ) , as occurs in cardiac arrest , causes a variable degree of neuronal damage and loss , depending upon the duration of the ischemia . in hippocampus , pyramidal neurons ( hpns ) in the ca1 subfield although adult hpns were previously felt to lack ca - ampa channels , especially in contrast to strongly ca - ampa channel expressing gabaergic interneurons , a number of studies have suggested that they may often be present under basal conditions in relatively low numbers , and preferentially on dendrites at a distance from the soma where they are not readily detected electrophysiologically ( lerma et al . , 1994 ; ikonomovic et al . , 1995 ; yin et al . , 1999 ; ogoshi and weiss , 2003 ) . in specific support of a role for ca - ampa channels in ischemic injury , maneuvers to increase numbers of these channels increased susceptibility of ca1 pyramidal neurons to ischemic injury , whereas decreasing channel numbers decreased injury ( anzai et al . a very intriguing clue to contributions of ca - ampa was provided by the observation that transient ischemia could induce a selective downregulation of glua2 mrna in ca1 pyramidal neurons , resulting in a delayed ( after 23  days ) incorporation of increased numbers ca - ampa channels into synapses ( gorter et al . , 1997 ; ; opitz et al . , 2000 ) . furthermore , indicating a direct role of these channels in the delayed neurodegeneration of ca1 neurons , the injury was attenuated by the delayed administration of a ca - ampa channel blocker ( noh et al . , 2005 ) . first , highlighting contributions of zn to ischemic neurodegeneration , zn accumulates in degenerating neurons and injury was attenuated by an extracellular zn chelator ( tonder et al . , 1990 ; koh et al . , 1996 ) . supporting a contribution of zn entry through ca - ampa channels , either an extracellular zn chelator or a ca - ampa channel blocker attenuated neuronal zn accumulation and subsequent degeneration in a hippocampal slice model of ischemia ( yin et al . , 2002 ) . interestingly , zn may act in distinct ways during different temporal phases of the ischemic process . addition of an extracellular zn chelator before the ischemic episode attenuated the glua2 downregulation , preventing the delayed increase in ca - ampa channels ( calderone et al . , 2004 ) . a number of recent studies suggest that mitochondria might be an important target of these early zn rises ( calderone et al . , 2004 ; these acute events appear to result in upregulation of the gene silencing transcription factor neuronal repressor element-1 silencing transcription factor ( rest)/neuron - restrictive silencer factor ( nrsf ) , which has been linked to the delayed downregulation of glua2 ( calderone et al . , 2003 ) . in contrast , late addition of either the chelator or of a ca - ampa channel blocker , after the channel upregulation was already underway , attenuated the occurrence of a delayed intracellular zn rise and associated cell death ( calderone et al . , 2004 ; noh et al . , 2005 ) , consistent with the idea that zn entry through the newly inserted channels might contribute to the delayed injury . of note , however , it is clear that not all ischemic zn accumulation reflects entry through ca - ampa or other channels , and that there are stores of zn already present in the ca1 neurons which can be mobilized in response to acidosis and oxidative stress associated with ischemia , contributing to the rises ( aizenman et al . , 2000 ; whereas downregulation of glua2 results in the incorporation of new ca - ampa channels after a significant delay , other recent studies have suggested that ischemia can also induce a more rapid endocytosis of ca impermeable ampa channels and exocytosis of ca - ampa channels into synapses via mechanisms involving receptor trafficking events that may be involved in synaptic plasticity ( liu et al . , 2006 ; dixon et al . , another study suggested that defects in glua2 editing may occur after ischemia , resulting in the incorporation of unedited glua2 into channels , rendering them ca permeable ( peng et al . , 2006 ) . interestingly , ampa receptors containing unedited glua2 may be particularly toxic to neurons , in part because of their constitutive trafficking to the plasma membrane ( mahajan and ziff , 2007 ) . amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive weakness due to the relatively selective degeneration of upper and lower mns , usually leading to death within 25  years of diagnosis . whereas most cases are sporadic , 10% are familial , and of those a fraction observations of loss of the ability of astrocytes to take up extracellular glutamate provided an early clue that excitotoxicity might contribute to the mn injury . consistent with this idea , glutamate uptake blockers caused preferential loss of mns both in organotypic slice and dissociated culture models ( rothstein et al . furthermore , supporting a role of ampa / kainate receptors in the disease , this mn degeneration was prevented by ampa / kainate blockers , but not by nmda blockers . first , they possess substantial numbers of ca - ampa channels ( carriedo et al . , 1996 ; van den bosch et al . , 2000 ; vandenberghe et al . , 2000 ) . in addition , populations of mns that degenerate in als are characterized by having low levels of cytosolic ca buffering proteins ( alexianu et al . , 1994 ; elliott and snider , 1995 ) , and buffer cytosolic ca loads poorly ( vanselow and keller , 2000 ) , such that excitotoxically induced ca loads are rapidly taken up into the mitochondria , with consequent strong mitochondrial ros release ( carriedo et al . , 2000 ) . in further studies , we have found evidence that this mitochondrial ros might not only damage the mns , but also exit the mns and contribute to the loss or dysfunction of glutamate transporters on surrounding astrocytes ( rao et al . , 2003 ) . such a mechanism might contribute to the propagation of a feed forward cascade , with loss of glutamate transport resulting in increased extracellular glutamate levels , more activation of ca - ampa channels , and more mitochondrial ca loading resulting in more ros generation ( rao and weiss , 2004 ; yin et al . , 2007 ) . transgenic mice overexpressing familial als associated sod1 mutations have provided by far the most studied animal models of the disease . providing strong evidence that ca - ampa channels play a role in this form of the disease , generation of sod1 mutant mice with increased numbers of ca - ampa channels in their mns accelerates disease progression , while decreasing numbers of the channels in these mice slows the disease ( tateno et al . , 2004 ; kuner et al . , 2005 ; van damme et al . , 2005 ) . in addition to the presence of some ca - ampa channels on mns under basal conditions , an intriguing series of studies suggests that there may be a loss of glua2 editing in als mns , such that numbers of ca - ampa channels may increase , further predisposing them to injury ( kawahara et al . , ampa receptors containing unedited glua2 may be particularly effective at inducing neurotoxicity ( mahajan and ziff , 2007 ) . another recent study suggests that the loss of glua2 editing may be triggered as a consequence of excitotoxic exposures , via proteolytic cleavage of the editing enzyme , rna - dependent adenosine deaminase , adar2 ( mahajan et al . , 2011 ) . although roles of ca - ampa channels have been most studied in the cases of ischemia and als , there are compelling clues to contributions in other conditions as well . first , ca - ampa channels may well contribute to neurodegeneration in conditions of prolonged seizures , or brain , or spinal cord trauma , both of which , like ischemia are associated with prolonged elevations of extracellular glutamate . much as in ischemia , glua2 mrna , and protein levels have been observed to decrease following prolonged seizures in ca1 and ca3 hippocampal pyramidal neurons prior to the death of these cells ( friedman et al . , 1994 ; grooms et al . , 2000 ) . in the case of traumatic injury , ventral root avulsion induced loss of glua2 in spinal mns ( nagano et al . , 2003 ) and spinal cord contusion caused preferential loss of glua2 in mns that persisted for at least a month ( grossman et al . in addition , recent studies in models of cerebral trauma provide evidence for endocytosis of glua2 containing receptors and insertion of ca - ampa receptors that contributed to the induction of injury ( spaethling et al . , 2008 ; bell et al . , 2009 ) other studies suggest possible contributions of ca - ampa channels to neurodegeneration in alzheimer s disease . cholinergic neurons of the basal forebrain conspicuously degenerate in alzheimer s disease ( whitehouse et al . , 1982 ) , and there is evidence for loss of other subpopulations of interneurons including those containing parvalbumin or somatostatin ( davies et al . , 1980 ; rossor et al . interestingly , in vitro studies indicate that these populations are all selectively sensitive to ampa / kainate receptor mediated excitotoxicity , probably in large part due to their possession of substantial numbers of ca - ampa channels ( weiss et al . , 1990 , 1994 ; yin et al . other studies have found glua2 on basal forebrain cholinergic neurons to be markedly decreased in aged humans ( ikonomovic et al . , 2000 ) , and that levels of glua2 on pyramidal neurons in the entorhinal cortex and hippocampus of alzheimer brains decrease prior to neurofibrillary tangle formation ( ikonomovic et al . , 1997 ) , suggesting that increased numbers of ca - ampa channels may predispose to the degeneration of these neuronal populations . further intriguing studies suggest a link between inflammation and increases in ca - ampa channel numbers . the inflammatory cytokine , tissue necrosis factor - alpha ( tnf- ) can lead to rapid exocytosis of ca - ampa channels on pyramidal neurons ( beattie et al . 2005 ) , and recent studies strongly suggest that tnf- dependent trafficking of ca - ampa channels contributes to neurodegeneration after spinal cord trauma ( ferguson et al . , 2008 ) . this mechanism could prove relevant to neurodegeneration in other immune or neurodegenerative conditions in which acute or chronic inflammation occurs . the past two decades have seen the accumulation of a host of clues to contributions of ca - ampa channels in a wide range of diseases of the nervous system . the presence of ca - ampa channels is not felt to be causative of the diseases . but the preferential expression of ca - ampa channels on subpopulations of neurons may be a factor in the selective patterns of neurodegeneration seen in certain conditions . in addition , the propensity for the upregulation of ca - ampa channel numbers , likely via a range of mechanisms , in response to disease associated signals may well subject affected neurons to new stresses that may tip the balance toward degeneration . despite the accumulation of numerous clues to roles of ca - ampa channels in disease , many questions , and obstacles exist . there are as yet no proven therapeutics based on the modulation or block of these channels . this likely reflects the absence to date of any highly effective , selective , and bioavailable drugs for blocking ca - ampa channels in whole animals , as would be necessary to fully test their contributions to disease . such blockers , if available , might be remarkably useful neuroprotectants in a wide range of conditions , as they may effectively antagonize toxic ca and zn entry through these channels without overly suppressing overall glutamatergic neurotransmission . the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .