Ca2+ Permeable AMPA Channels in Diseases of the Nervous System

REVIEW ARTICLE published: 14 November 2011 MOLECULAR NEUROSCIENCE doi: 10.3389/fnmol.2011.00042 Ca2+ permeable AMPA channels in diseases of the nervous system

John H. Weiss 1,2*

1 Department of Neurology, University of California Irvine, Irvine, CA, USA 2 Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA

Edited by: Since the discovery and molecular characterization of Ca2+-permeable AMPA channels just R. Suzanne Zukin, Albert Einstein over two decades ago, a large body of evidence has accumulated implicating contributions College of Medicine, USA of these unusual glutamate activated channels to selective neurodegeneration in certain Reviewed by: KeWei Wang, Peking University, China conditions, including ischemia and amyotrophic lateral sclerosis. Factors likely involved in Frantisek Jursky, Slovak Academy of their contributions to disease include their distinct patterns of expression in certain neuronal Sciences, Slovak Republic populations, their upregulation via various mechanisms in response to disease associated + + *Correspondence: stresses, and their high permeability to Zn2 as well as to Ca2 . However, full characteriza- John H. Weiss, Department of tion of their contributions to certain diseases as well as development of therapeutics has Neurology, University of California Irvine, Irvine, CA 92697, USA. been limited by the lack of selective and bioavailable blockers of these channels that can e-mail: [email protected] be employed in animals or humans. This review summarizes some of the clues that have emerged over recent years to the contributions of these channels in disease.

Keywords: calcium, zinc, ALS, motor neuron, neurodegeneration, glutamate, excitotoxicity

INTRODUCTION beta-N -oxalylamino-l-alanine (BOAA), and domoic acid Glutamate is the main excitatory transmitter in the mammalian (Spencer et al., 1986, 1987; Teitelbaum et al., 1990). BOAA and central nervous system. Overactivation of post-synaptic receptors domoic acid, the respective causes of lathyrism and a form of for glutamate places a metabolic stress upon neurons which can shellfish poisoning, are both well established AMPA/kainate recep- contribute to neuronal injury in a wide range of conditions. The tor agonists. BMAA, an unusual cyanobacterial toxin suspected of evidence for a contribution of glutamate receptor overactivation contributing to forms of human neurodegenerative disease, can (termed “excitotoxicity”) is strongest in conditions like ischemia, induce selective injury to vulnerable subpopulations of neurons, prolonged seizures, and trauma, in which there is rapid release including motor neurons (MN, which degenerate in ALS), via acti- and extracellular accumulation of glutamate. However, there is vation of AMPA/kainate receptors (Weiss et al., 1989; Weiss and also compelling evidence for important excitotoxic contributions Choi, 1991; Rao et al., 2006). Whereas most AMPA/kainate type to injury in neurodegenerative conditions including amyotrophic glutamate channels are Ca2+ impermeable, subsets of these chan- lateral sclerosis (ALS). nels, which are expressed in characteristic temporal and spatial Glutamate acts at a number of receptors comprising both lig- patterns on discrete populations of neurons, are Ca2+-permeable, and gated ion channels (ionotropic receptors) and g-protein linked and it is the activation of these channels that likely mediates most (metabotropic) receptors. Three families of ionotropic glutamate of the neurodegeneration attributable to AMPA/kainate receptor receptors (NMDA, AMPA, and kainate receptors) have been char- activation. This review focuses specifically on Ca2+-permeable acterized both pharmacologically and by the identification and AMPA (Ca-AMPA) channels and clues that have accumulated cloning of their subunit genes. Early studies of excitotoxic mech- over the past two decades to their roles in both acute and chronic anisms focused on possible contributions of NMDA receptors, neurodegenerative conditions. which unlike most AMPA, and kainate receptors (collectively referred to as AMPA/kainate receptors), are highly permeable STRUCTURE AND REGULATION OF Ca-AMPA CHANNELS to Ca2+ ions, and brief activation of which could potently trig- AMPA channels are the most prevalent glutamate channels in the ger delayed injury to cultured neurons. However, despite clear mammalian central nervous system, and mediate most routine contributions of these channels in some models of acute neu- excitatory neurotransmission. They are tetramers comprised of rodegeneration, NMDA blockers have to date failed to show combinations of four subunits – GluA (previously referred to as impressive efficacy in therapeutic trials. Furthermore, in some GluR) 1, 2, 3, or 4. The presence of one or more GluA2 subunits studies AMPA/kainate receptor blockade has shown greater effi- in a heteromeric channel prevents Ca2+ permeability. The abil- cacy against ischemic injury than NMDA receptor antagonism ity of GluA2 subunits to block Ca2+ permeability is dependent (Buchan et al., 1993). upon the presence of a positively charged arginine residue at a Another early clue to contributions of AMPA/kainite in critical site in the channel lining region of the peptide (the “Q/R neurodegeneration derives from studies of syndromes in site”); the other AMPA subunits (GluR1, 3, and 4) all have a neu- humans or primates linked to the consumption of envi- tral glutamine at the homologous site. Interestingly, the genomic ronmental toxins, beta-N -methylamino-l-alanine (BMAA), DNA encodes a neutral glutamine residue at this site in all four

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 1 Weiss Ca-AMPA channels in CNS disease

subunits, and the arginine codon is post-transcriptionally inserted plasticity. In contrast,Ca-AMPAchannels are not blocked by extra- into the GluA2 mRNA transcript via RNA editing by the enzyme cellular cations (but are subject to voltage dependent block by ADAR2 (Higuchi et al., 2000). After translation, the subunits are intracellular polyamines,resulting in inwardly rectifying currents), assembled in the ER. Likely indicative of the critical importance of and thus freely permit Ca2+ entry with any level of receptor acti- these channels to normal physiological function,channel assembly, vation. Secondly, whereas the expression of NMDA channels is and membrane insertion are both sensitive to the editing state of relatively static, AMPA channels are strongly regulated in response GluA2 (Greger et al., 2002, 2003; Araki et al., 2010). It has further to physiological and pathological signals, and numbers of Ca- become apparent that pathological upregulation of these chan- AMPA channels may increase sharply in certain stress conditions nels in disease states can occur via several mechanisms, including and disease states (as discussed further below). Thus, the increase downregulation of GluA2 mRNA transcription, defective editing in numbers of these channels in already stressed neurons adds of the GluA2 pre-mRNA, and aberrant internalization of GluA2 an additional metabolic burden that may impair their ability to containing (and Ca2+ impermeable) channels and insertion of restore homeostasis and survive. GluA2 lacking channels. A likely third factor in their propensity to contribute to injury The presence of Ca-AMPAchannels is neither uniform nor con- concerns their permeability to other divalent cations. Zn2+ is stant, but varies with cell type and developmental stage. Whereas present in pre-synaptic vesicles of many (but not all) forebrain most adult neurons possess relatively few of these channels, dis- excitatory pathways, and appears to be co-released with glutamate crete populations of neurons, most prominently many GABAergic upon pre-synaptic activation (Assaf and Chung, 1984; Howell inhibitory interneurons,possess large numbers of Ca-AMPAchan- et al., 1984; Qian and Noebels, 2005). Although the physiological nels (Jonas et al., 1994; Yin et al., 1994a; Leranth et al., 1996). In significance of pre-synaptic Zn2+ release is uncertain, it can effec- contrast most adult excitatory pyramidal neurons possess few of tively block NMDA channels, limiting their ion flux in response to these channels. However, numbers of Ca-AMPA channels on pyra- intense pre-synaptic activation (Paoletti et al., 2009). In contrast, midal neurons change with developmental stage, and are present Zn2+ readily permeates Ca-AMPA channels (Jia et al., 2002), and in markedly increased numbers in both rats and humans in early its entry through these channels can clearly injure cultured neu- postnatal periods (Kumar et al., 2002; Talos et al., 2006a,b; Brill rons and likely contributes to injury in conditions like ischemia and Huguenard, 2008). (Yin and Weiss, 1995; Sensi et al., 1999; Yin et al., 2002; Calderone et al., 2004; Noh et al., 2005). Intracellular Zn2+ can trigger neu- MECHANISMS OF INJURY CAUSED BY Ca-AMPA CHANNELS rodegeneration via a number of mechanisms, including some As mentioned above, relatively brief but strong activation of highly previously attributed to Ca2+, including the induction of mito- Ca2+ permeable NMDA channels is sufficient to trigger degener- chondrial dysfunction, which it appears to do with considerably ation of cultured neurons. A large number of studies have high- greater potency than Ca2+ (Sensi et al., 2009; Shuttleworth and lighted mechanisms through which such neuronal Ca2+ loading Weiss, 2011). can induce injury, which may vary depending upon the intensity of the Ca2+ load. With strong loading, Ca2+ is taken up into mito- Ca-AMPA CHANNELS IN ISCHEMIC NEURODEGENERATION chondria and can disrupt their function, causing release of damag- As mentioned above, some early studies found AMPA/kainate ing reactive oxygen species (ROS; Dugan et al., 1995; Reynolds and blockers to provide greater protection than NMDA blockers Hastings,1995). In addition,Ca2+ loading can induce ROS genera- against ischemic neurodegeneration, and it is likely that much tion through other mechanisms, including the activation of nitric of this protection reflects blockade of Ca-AMPA channels. Studies oxide synthetase (NOS), with resultant nitric oxide production, to date have suggested that Ca-AMPA channels may contribute to and the activation of NADPH-oxidase, with resultant superox- different forms of ischemic injury in a number of ways. ide production (Dawson et al., 1991; Brennan et al., 2009). These The immature brain is particularly susceptible to ischemia, and ROS may induce DNA damage, causing activation of the enzyme, pre-term, or perinatal hypoxia ischemia of both white and gray PARP, which can injure neurons via NAD+ depletion, resulting matter is a major cause of early life morbidity, for instance as in glycolytic block, depletion of ATP, and induction of apoptotic an antecedent of cerebral palsy. A number of studies have indi- signaling via release of AIF from mitochondria (Hong et al., 2004; cated that periods of high ischemic susceptibility correspond to Alano et al., 2010). developmental periods of increased Ca-AMPA channel numbers, It appears likely that many of these same downstream mecha- suggesting that the presence of these channels contributes to the nisms may apply to injury caused by strong activation of Ca-AMPA ischemic susceptibility (Talos et al., 2006a,b). channels (Carriedo et al., 1998). A key question thus concerns dif- Transient global ischemia (TGI), as occurs in cardiac arrest, ferences between NMDA and Ca-AMPA dependent injury, possi- causes a variable degree of neuronal damage and loss, depending bly accounting for the apparent greater contributions of Ca-AMPA upon the duration of the ischemia. In hippocampus, pyramidal channels in some conditions. One difference is that NMDA chan- neurons (HPNs) in the CA1 subfield are particularly susceptible. nels are subject to a voltage dependent block of their pores by Although adult HPNs were previously felt to lack Ca-AMPA chan- extracellular Mg2+ ions, such that there is relatively little ion flux nels, especially in contrast to strongly Ca-AMPA channel express- through these channels in the absence of significant post-synaptic ing GABAergic interneurons, a number of studies have suggested depolarization. This voltage dependence allows NMDA channels that they may often be present under basal conditions in relatively to detect temporally and spatially convergent post-synaptic inputs low numbers, and preferentially on dendrites at a distance from and is thus important to their roles in activity dependent synaptic the soma where they are not readily detected electrophysiologically

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 2 Weiss Ca-AMPA channels in CNS disease

(Lerma et al., 1994; Ikonomovic et al., 1995;Yin et al., 1999; Ogoshi in the incorporation of unedited GluA2 into channels, render- and Weiss, 2003). ing them Ca2+ permeable (Peng et al., 2006). Interestingly, AMPA In specific support of a role for Ca-AMPA channels in ischemic receptors containing unedited GluA2 may be particularly toxic to injury, maneuvers to increase numbers of these channels increased neurons, in part because of their constitutive trafficking to the susceptibility of CA1 pyramidal neurons to ischemic injury, plasma membrane (Mahajan and Ziff, 2007). whereas decreasing channel numbers decreased injury (Anzai et al., 2003; Liu et al., 2004). A very intriguing clue to con- Ca-AMPA CHANNELS IN ALS tributions of Ca-AMPA was provided by the observation that Amyotrophic lateral sclerosis is a neurodegenerative disease char- transient ischemia could induce a selective downregulation of acterized by progressive weakness due to the relatively selective GluA2 mRNA in CA1 pyramidal neurons, resulting in a delayed degeneration of upper and lower MNs, usually leading to death (after 2–3 days) incorporation of increased numbers Ca-AMPA within 2–5 years of diagnosis. Whereas most cases are sporadic, channels into synapses (Gorter et al., 1997; Pellegrini-Giampietro ∼10% are familial, and of those a fraction are linked to dom- et al., 1997; Grooms et al., 2000; Opitz et al., 2000). Further- inant mutations in the gene superoxide dismutase 1 (SOD1). more, indicating a direct role of these channels in the delayed Observations of loss of the ability of astrocytes to take up extracel- neurodegeneration of CA1 neurons, the injury was attenuated by lular glutamate provided an early clue that excitotoxicity might the delayed administration of a Ca-AMPA channel blocker (Noh contribute to the MN injury. Consistent with this idea, gluta- et al., 2005). mate uptake blockers caused preferential loss of MNs both in Further studies point toward intriguing roles of Zn2+ in organotypic slice and dissociated culture models (Rothstein et al., this form of injury. First, highlighting contributions of Zn2+ 1993; Carriedo et al., 1996). Furthermore, supporting a role of to ischemic neurodegeneration, Zn2+ accumulates in degenerat- AMPA/kainate receptors in the disease, this MN degeneration was ing neurons and injury was attenuated by an extracellular Zn2+ prevented by AMPA/kainate blockers, but not by NMDA blockers. chelator (Tonder et al., 1990; Koh et al., 1996). Supporting a con- We and others have investigated mechanisms underlying the tribution of Zn2+ entry through Ca-AMPA channels, either an excitotoxic vulnerability of MNs. First, they possess substantial extracellular Zn2+ chelator or a Ca-AMPA channel blocker atten- numbers of Ca-AMPA channels (Carriedo et al., 1996; Van Den uated neuronal Zn2+ accumulation and subsequent degeneration Bosch et al., 2000; Vandenberghe et al., 2000). In addition, pop- in a hippocampal slice model of ischemia (Yin et al., 2002). Inter- ulations of MNs that degenerate in ALS are characterized by estingly, Zn2+ may act in distinct ways during different temporal having low levels of cytosolic Ca2+ buffering proteins (Alexianu phases of the ischemic process. Addition of an extracellular Zn2+ et al., 1994; Elliott and Snider, 1995), and buffer cytosolic Ca2+ chelator before the ischemic episode attenuated the GluA2 down- loads poorly (Vanselow and Keller, 2000), such that excitotoxically regulation, preventing the delayed increase in Ca-AMPA channels induced Ca2+ loads are rapidly taken up into the mitochon- (Calderone et al., 2004). A number of recent studies suggest that dria, with consequent strong mitochondrial ROS release (Carriedo mitochondria might be an important target of these early Zn2+ et al., 2000). In further studies, we have found evidence that this rises (Calderone et al., 2004; Bonanni et al., 2006; Medvedeva et al., mitochondrial ROS might not only damage the MNs, but also exit 2009). These acute events appear to result in upregulation of the the MNs and contribute to the loss or dysfunction of glutamate gene silencing transcription factor neuronal repressor element-1 transporters on surrounding astrocytes (Rao et al., 2003). Such a silencing transcription factor (REST)/neuron-restrictive silencer mechanism might contribute to the propagation of a feed forward factor (NRSF), which has been linked to the delayed downregula- cascade, with loss of glutamate transport resulting in increased tion of GluA2 (Calderone et al., 2003). In contrast, late addition extracellular glutamate levels, more activation of Ca-AMPA chan- of either the chelator or of a Ca-AMPA channel blocker, after the nels, and more mitochondrial Ca2+ loading resulting in more ROS channel upregulation was already underway, attenuated the occur- generation (Rao and Weiss, 2004; Yin et al., 2007). rence of a delayed intracellular Zn2+ rise and associated cell death Transgenic mice overexpressing familial ALS associated SOD1 (Calderone et al., 2004; Noh et al., 2005), consistent with the idea mutations have provided by far the most studied animal models that Zn2+ entry through the newly inserted channels might con- of the disease. Providing strong evidence that Ca-AMPA channels tribute to the delayed injury. Of note, however, it is clear that not play a role in this form of the disease, generation of SOD1 mutant all ischemic Zn2+ accumulation reflects entry through Ca-AMPA mice with increased numbers of Ca-AMPA channels in their MNs or other channels, and that there are stores of Zn2+ already present accelerates disease progression, while decreasing numbers of the in the CA1 neurons which can be mobilized in response to acidosis channels in these mice slows the disease (Tateno et al., 2004; Kuner and oxidative stress associated with ischemia, contributing to the et al., 2005; Van Damme et al., 2005). rises (Aizenman et al., 2000; Lee et al., 2000). In addition to the presence of some Ca-AMPAchannels on MNs Whereas downregulation of GluA2 results in the incorporation under basal conditions, an intriguing series of studies suggests that of new Ca-AMPA channels after a significant delay, other recent there may be a loss of GluA2 editing in ALS MNs, such that num- studies have suggested that ischemia can also induce a more rapid bers of Ca-AMPA channels may increase, further predisposing endocytosis of Ca2+ impermeable AMPA channels and exocyto- them to injury (Kawahara et al., 2004; Kwak et al., 2010). As men- sis of Ca-AMPA channels into synapses via mechanisms involving tioned above, AMPA receptors containing unedited GluA2 may be receptor trafficking events that may be involved in synaptic plas- particularly effective at inducing neurotoxicity (Mahajan and Ziff, ticity (Liu et al., 2006; Dixon et al., 2009). Another study suggested 2007). Another recent study suggests that the loss of GluA2 edit- that defects in GluA2 editing may occur after ischemia, resulting ing may be triggered as a consequence of excitotoxic exposures,

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 3 Weiss Ca-AMPA channels in CNS disease

via proteolytic cleavage of the editing enzyme, RNA-dependent Further intriguing studies suggest a link between inflammation adenosine deaminase, ADAR2 (Mahajan et al., 2011). and increases in Ca-AMPA channel numbers. The inflammatory cytokine, tissue necrosis factor-alpha (TNF-α) can lead to rapid Ca-AMPA CHANNELS IN OTHER CONDITIONS exocytosis of Ca-AMPA channels on pyramidal neurons (Beat- Although roles of Ca-AMPA channels have been most studied in tie et al., 2002; Ogoshi et al., 2005; Stellwagen et al., 2005), and the cases of ischemia and ALS, there are compelling clues to con- recent studies strongly suggest that TNF-α dependent traffick- tributions in other conditions as well. First, Ca-AMPA channels ing of Ca-AMPA channels contributes to neurodegeneration after may well contribute to neurodegeneration in conditions of pro- spinal cord trauma (Ferguson et al., 2008). This mechanism could longed seizures, or brain, or spinal cord trauma, both of which, like prove relevant to neurodegeneration in other immune or neu- ischemia are associated with prolonged elevations of extracellular rodegenerative conditions in which acute or chronic inflammation glutamate. Much as in ischemia, GluA2 mRNA, and protein lev- occurs. els have been observed to decrease following prolonged seizures in CA1 and CA3 hippocampal pyramidal neurons prior to the CONCLUSIONS death of these cells (Friedman et al., 1994; Grooms et al., 2000). In The past two decades have seen the accumulation of a host of the case of traumatic injury, ventral root avulsion induced loss of clues to contributions of Ca-AMPA channels in a wide range GluA2 in spinal MNs (Nagano et al., 2003) and spinal cord contu- of diseases of the nervous system. The presence of Ca-AMPA sion caused preferential loss of GluA2 in MNs that persisted for at channels is not felt to be causative of the diseases. But the pref- least a month (Grossman et al., 1999). In addition, recent studies erential expression of Ca-AMPA channels on subpopulations of in models of cerebral trauma provide evidence for endocytosis of neurons may be a factor in the selective patterns of neurode- GluA2 containing receptors and insertion of Ca-AMPA receptors generation seen in certain conditions. In addition, the propensity that contributed to the induction of injury (Spaethling et al., 2008; for the upregulation of Ca-AMPA channel numbers, likely via a Bell et al., 2009). range of mechanisms, in response to disease associated signals Other studies suggest possible contributions of Ca-AMPA may well subject affected neurons to new stresses that may tip channels to neurodegeneration in Alzheimer’s disease. Cholin- the balance toward degeneration. Despite the accumulation of ergic neurons of the basal forebrain conspicuously degenerate numerous clues to roles of Ca-AMPA channels in disease, many in Alzheimer’s disease (Whitehouse et al., 1982), and there is questions, and obstacles exist. There are as yet no proven thera- evidence for loss of other subpopulations of interneurons includ- peutics based on the modulation or block of these channels. This ing those containing parvalbumin or somatostatin (Davies et al., likely reflects the absence to date of any highly effective, selec- 1980; Rossor et al., 1980; Arai et al., 1987). Interestingly, in vitro tive, and bioavailable drugs for blocking Ca-AMPA channels in studies indicate that these populations are all selectively sensi- whole animals, as would be necessary to fully test their contribu- tive to AMPA/kainate receptor mediated excitotoxicity, probably tions to disease. Such blockers, if available, might be remarkably in large part due to their possession of substantial numbers of useful neuroprotectants in a wide range of conditions, as they + + Ca-AMPA channels (Weiss et al., 1990, 1994; Yin et al., 1994b). may effectively antagonize toxic Ca2 and Zn2 entry through Other studies have found GluA2 on basal forebrain cholinergic these channels without overly suppressing overall glutamatergic neurons to be markedly decreased in aged humans (Ikonomovic neurotransmission. et al., 2000), and that levels of GluA2 on pyramidal neurons in the entorhinal cortex and hippocampus of Alzheimer brains ACKNOWLEDGMENTS decrease prior to neurofibrillary tangle formation (Ikonomovic Supported by NIH grants NS36548 and NS065219. I would like to et al., 1997), suggesting that increased numbers of Ca-AMPA thank Dr. Hong Z. Yin for outstanding work concerning expres- 2+ channels may predispose to the degeneration of these neuronal sion patterns of Ca permeable AMPA channels, carried out over populations. the past 20 years in the lab.

REFERENCES and Appel, S. H. (1994). The role cortex in Alzheimer-type dementia. synaptic strength by glial TNFalpha. Aizenman, E., Stout, A. K., Hartnett, K. of calcium-binding proteins in selec- Brain Res. 418, Science 295, 2282–2285. A., Dineley, K. E., McLaughlin, B., tive motoneuron vulnerability in 164–169. Bell, J. D., Park, E., Ai, J., and Baker, and Reynolds, I. J. (2000). Induc- amyotrophic lateral sclerosis. Ann. Araki, Y., Lin, D. T., and Huganir, R. A. J. (2009). PICK1-mediated GluR2 tion of neuronal apoptosis by thiol Neurol. 36, 846–858. L. (2010). Plasma membrane inser- endocytosis contributes to cellular oxidation: putative role of intracel- Anzai, T., Tsuzuki, K., Yamada, N., tion of the AMPA receptor GluA2 injury after neuronal trauma. Cell lular zinc release. J. Neurochem. 75, Hayashi, T., Iwakuma, M., Inada, K., subunit is regulated by NSF bind- Death Differ. 16, 1665–1680. 1878–1888. Kameyama, K., Hoka, S., and Saji, ing and Q/R editing of the ion pore. Bonanni, L., Chachar, M., Jover- Alano, C. C., Garnier, P., Ying, W., M. (2003). Overexpression of Ca2+- Proc. Natl. Acad. Sci. U.S.A. 107, Mengual, T., Li, H., Jones, A.,Yokota, Higashi, Y., Kauppinen, T. M., permeableAMPA receptor promotes 11080–11085. H., Ofengeim, D., Flannery, R. J., and Swanson, R. A. (2010). delayed cell death of hippocam- Assaf, S. Y., and Chung, S. H. (1984). Miyawaki, T., Cho, C. H., Polster, NAD+ depletion is necessary pal CA1 neurons following transient Release of endogenous Zn2+ from B. M., Pypaert, M., Hardwick, J. and sufﬁcient for poly(ADP- forebrain ischemia. Neurosci. Res. 46, brain tissue during activity. Nature M., Sensi, S. L., Zukin, R. S., and ribose) polymerase-1-mediated 41–51. 308, 734–736. Jonas, E. A. (2006). Zinc-dependent neuronal death. J. Neurosci. 30, Arai, H., Emson, P. C., Mountjoy, C. Beattie, E. C., Stellwagen, D., Morishita, multi-conductance channel activ- 2967–2978. Q., Carassco, L. H., and Heizmann, W., Bresnahan, J. C., Ha, B. K., ity in mitochondria isolated from Alexianu, M. E., Ho, B. K., Mohamed, C. W. (1987). Loss of parvalbumin- Von Zastrow, M., Beattie, M. S., and ischemic brain. J. Neurosci. 26, A. H., La Bella, V., Smith, R. G., immunoreactive neurones from Malenka, R. C. (2002). Control of 6851–6862.

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 4 Weiss Ca-AMPA channels in CNS disease

Brennan, A. M., Suh, S. W., Won, S. J., in oxygen/glucose-deprived hip- the RNA-editing enzyme ADAR2. Proc. Natl. Acad. Sci. U.S.A. 102, Narasimhan, P., Kauppinen, T. M., pocampal neurons. J. Biol. Chem. Nature 406, 78–81. 5826–5831. Lee, H., Edling, Y., Chan, P. H., and 284, 14230–14235. Hong, S. J., Dawson, T. M., and Dawson, Kwak, S., Hideyama, T., Yamashita, Swanson, R. A. (2009). NADPH oxi- Dugan, L. L., Sensi, S. L., Canzoniero, V. L. (2004). Nuclear and mitochon- T., and Aizawa, H. (2010). AMPA dase is the primary source of super- L. M., Handran, S. D., Rothman, drial conversations in cell death: receptor-mediated neuronal death oxide induced by NMDA recep- S. M., Lin, T. S., Goldberg, M. P., PARP-1 and AIF signaling. Trends in sporadic ALS. Neuropathology 30, tor activation. Nat. Neurosci. 12, and Choi, D. W. (1995). Mitochon- Pharmacol. Sci. 25, 259–264. 182–188. 857–863. drial production of reactive oxygen Howell, G. A., Welch, M. G., and Fred- Lee, J. Y., Cole, T. B., Palmiter, R. D., Brill, J., and Huguenard, J. R. species in cortical neurons following erickson, C. J. (1984). Stimulation- and Koh, J. Y. (2000). Accumulation (2008). Sequential changes in exposure to N -methyl-d-aspartate. induced uptake and release of zinc of zinc in degenerating hippocam- AMPA receptor targeting in the J. Neurosci. 15, 6377–6388. in hippocampal slices. Nature 308, pal neurons of ZnT3-null mice after developing neocortical exci- Elliott, J. L., and Snider, W. D. (1995). 736–738. seizures: evidence against synap- tatory circuit. J. Neurosci. 28, Parvalbumin is a marker of ALS- Ikonomovic, M. D., Mizukami, K., tic vesicle origin. J. Neurosci. 20, 13918–13928. resistant motor neurons. Neurore- Davies, P., Hamilton, R., Sheffield, RC79. Buchan, A. M., Lesiuk, H., Barnes, K. port 6, 449–452. R., and Armstrong, D. M. (1997). Leranth, C., Szeidemann, Z., Hsu, M., A., Li, H., Huang, Z. G., Smith, Ferguson, A. R., Christensen, R. N., The loss of GluR2(3) immunoreac- and Buzsaki, G. (1996). AMPA K. E., and Xue, D. (1993). AMPA Gensel, J. C., Miller, B. A., Sun, F., tivity precedes neurofibrillary tan- receptors in the rat and primate antagonists: do they hold more Beattie, E. C., Bresnahan, J. C., and gle formation in the entorhinal cor- hippocampus: a possible absence of promise for clinical stroke trials Beattie, M. S. (2008). Cell death after tex and hippocampus of Alzheimer GluR2/3 subunits in most interneu- than NMDA antagonists? Stroke 24, spinal cord injury is exacerbated by brains. J. Neuropathol. Exp. Neurol. rons. Neuroscience 70, 631–652. I148–I152. rapid TNF alpha-induced traffick- 56, 1018–1027. Lerma, J., Morales, M., Ibarz, J. M., and Calderone, A., Jover, T., Mashiko, T., ing of GluR2-lacking AMPARs to the Ikonomovic, M. D., Nocera, R., Somohano, F. (1994). Rectification Noh, K. M., Tanaka, H., Bennett, plasma membrane. J. Neurosci. 28, Mizukami, K., and Armstrong, D. properties and Ca2+ permeability M. V., and Zukin, R. S. (2004). 11391–11400. M. (2000). Age-related loss of the of glutamate receptor channels in Late calcium EDTA rescues hip- Friedman, L. K., Pellegrini-Giampietro, AMPA receptor subunits GluR2/3 hippocampal cells. Eur. J. Neurosci. pocampal CA1 neurons from global D. E., Sperber, E. F., Bennett, M. V., in the human nucleus basalis of 6, 1080–1088. ischemia-induced death. J. Neurosci. Moshe, S. L., and Zukin, R. S. (1994). Meynert. Exp. Neurol. 166, 363–375. Liu, B., Liao, M., Mielke, J. G., Ning, 24, 9903–9913. Kainate-induced status epilepticus Ikonomovic, M. D., Sheffield, R., and K., Chen, Y., Li, L., El-Hayek, Y. H., Calderone, A., Jover, T., Noh, K. M., alters glutamate and GABAA recep- Armstrong, D. M. (1995). AMPA- Gomez, E., Zukin, R. S., Fehlings, M. Tanaka, H., Yokota, H., Lin, Y., tor gene expression in adult rat hip- selective glutamate receptor sub- G., and Wan, Q. (2006). Ischemic Grooms, S. Y., Regis, R., Bennett, M. pocampus: an in situ hybridization type immunoreactivity in the aged insults direct glutamate receptor V., and Zukin, R. S. (2003). Ischemic study. J. Neurosci. 14, 2697–2707. human hippocampal formation. J. subunit 2-lacking AMPA receptors insults derepress the gene silencer Gorter, J. A., Petrozzino, J. J., Aronica, Comp. Neurol. 359, 239–252. to synaptic sites. J. Neurosci. 26, REST in neurons destined to die. J. E. M., Rosenbaum, D. M., Opitz, Jia, Y., Jeng, J. M., Sensi, S. L., and 5309–5319. Neurosci. 23, 2112–2121. T., Bennett, M. V., Connor, J. A., Weiss, J. H. (2002). Zn2+ currents Liu, S., Lau, L., Wei, J., Zhu, D., Carriedo, S. G., Sensi, S. L., Yin, H. Z., and Zukin, R. S. (1997). Global are mediated by calcium-permeable Zou, S., Sun, H. S., Fu, Y., Liu, F., and Weiss, J. H. (2000). AMPA expo- ischemia induces downregulation of AMPA/kainate channels in cultured and Lu, Y. (2004). Expression of sures induce mitochondrial Ca(2+) Glur2 mRNA and increases AMPA murine hippocampal neurones. J. Ca(2+)-permeable AMPA receptor overload and ROS generation in receptor-mediated Ca2+ influx in Physiol. 543, 35–48. channels primes cell death in tran- spinal motor neurons in vitro. J. hippocampal CA1 neurons of gerbil. Jonas, P., Racca, C., Sakmann, B., See- sient forebrain ischemia. Neuron 43, Neurosci. 20, 240–250. J. Neurosci. 17, 6179–6188. burg, P. H., and Monyer, H. (1994). 43–55. Carriedo, S. G., Yin, H. Z., Sensi, Greger, I. H., Khatri, L., Kong, X., and Differences in Ca2+ permeabil- Mahajan, S. S., Thai, K. H., Chen, K., S. L., and Weiss, J. H. (1998). Ziff, E. B. (2003). AMPA receptor ity of AMPA-type glutamate recep- and Ziff, E. (2011). Exposure of neu- Rapid Ca2+ entry through Ca2+- tetramerization is mediated by Q/R tor channels in neocortical neurons to excitotoxic levels of gluta- permeable AMPA/Kainate channels editing. Neuron 40, 763–774. rons caused by differential GluR- mate induces cleavage of the RNA triggers marked intracellular Ca2+ Greger, I. H., Khatri, L., and Ziff, E. B. B subunit expression. Neuron 12, editing enzyme, adenosine deami- rises and consequent oxygen rad- (2002). RNA editing at arg607 con- 1281–1289. nase acting on RNA 2, and loss of ical production. J. Neurosci. 18, trols AMPA receptor exit from the Kawahara,Y.,Ito,K.,Sun,H.,Aizawa,H., GLUR2 editing. Neuroscience 189, 7727–7738. endoplasmic reticulum. Neuron 34, Kanazawa, I., and Kwak, S. (2004). 305–315. Carriedo, S. G., Yin, H. Z., and Weiss, J. 759–772. Glutamate receptors: RNA editing Mahajan, S. S., and Ziff, E. B. (2007). H. (1996). Motor neurons are selec- Grooms, S. Y., Opitz, T., Bennett, and death of motor neurons. Nature Novel toxicity of the unedited GluR2 tively vulnerable to AMPA/kainate M. V., and Zukin, R. S. (2000). 427, 801. AMPA receptor subunit dependent receptor-mediated injury in vitro. J. Status epilepticus decreases gluta- Koh, J. Y., Suh, S. W., Gwag, B. J., He, Y. on surface trafficking and increased Neurosci. 16, 4069–4079. mate receptor 2 mRNA and protein Y.,Hsu,C.Y.,and Choi,D. W.(1996). Ca2+-permeability. Mol. Cell. Neu- Davies, P., Katzman, R., and Terry, R. D. expression in hippocampal pyra- The role of zinc in selective neuronal rosci. 35, 470–481. (1980). Reduced somatostatin-like midal cells before neuronal death. death after transient global cerebral Medvedeva, Y. V., Lin, B., Shuttle- immunoreactivity in cerebral cortex Proc. Natl. Acad. Sci. U.S.A. 97, ischemia. Science 272, 1013–1016. worth, C. W., and Weiss, J. H. from cases of Alzheimer disease and 3631–3636. Kumar, S. S., Bacci, A., Kharazia, V., and (2009). Intracellular Zn2+ accu- Alzheimer senile dementa. Nature Grossman, S. D., Wolfe, B. B., Yasuda,R. Huguenard, J. R. (2002). A devel- mulation contributes to synap- 288, 279–280. P., and Wrathall, J. R. (1999). Alter- opmental switch of AMPA receptor tic failure, mitochondrial depo- Dawson, V. L., Dawson, T. M., London, ations in AMPA receptor subunit subunits in neocortical pyramidal larization, and cell death in an E. D., Bredt, D. S., and Snyder, S. H. expression after experimental spinal neurons. J. Neurosci. 22, 3005–3015. acute slice oxygen-glucose depriva- (1991). Nitric oxide mediates gluta- cord contusion injury. J. Neurosci. Kuner, R., Groom, A. J., Bresink, I., tion model of ischemia. J. Neurosci. mate neurotoxicity in primary cor- 19, 5711–5720. Kornau, H. C., Stefovska, V., Muller, 29, 1105–1114. tical cultures. Proc. Natl. Acad. Sci. Higuchi, M., Maas, S., Single, F. N., G., Hartmann, B., Tschauner, K., Nagano, I., Murakami, T., Shiote, M., U.S.A. 88, 6368–6371. Hartner, J., Rozov, A., Burnashev, Waibel, S., Ludolph, A. C., Ikonomi- Abe, K., and Itoyama,Y. (2003). Ven- Dixon, R. M., Mellor, J. R., and Hanley, N., Feldmeyer, D., Sprengel, R., and dou, C., Seeburg, P. H., and Turski, tral root avulsion leads to downreg- J. G. (2009). PICK1-mediated glu- Seeburg, P. H. (2000). Point muta- L. (2005). Late-onset motoneuron ulation of GluR2 subunit in spinal tamate receptor subunit 2 (GluR2) tion in an AMPA receptor gene res- disease caused by a functionally motoneurons in adult rats. Neuro- trafficking contributes to cell death cues lethality in mice deficient in modified AMPA receptor subunit. science 117, 139–146.

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 5 Weiss Ca-AMPA channels in CNS disease

Noh, K. M., Yokota, H., Mashiko, T., between motor neurons and glia in necrosis factor-alpha. J. Neurosci. 25, calcium permeability, GluR2 expres- Castillo, P. E., Zukin, R. S., and ALS pathogenesis. Trends Neurosci. 3219–3228. sion, and selective motoneuron vul- Bennett, M. V. (2005). Blockade of 27, 17–23. Talos, D. M., Follett, P. L., Folkerth, nerability. J. Neurosci. 20, 123–132. calcium-permeable AMPA receptors Rao, S. D., Yin, H. Z., and Weiss, R. D., Fishman, R. E., Trachten- Vanselow, B. K., and Keller, B. U. (2000). protects hippocampal neurons J. H. (2003). Disruption of glial berg, F. L., Volpe, J. J., and Jensen, Calcium dynamics and buffering in against global ischemia-induced glutamate transport by reac- F. E. (2006a). Developmental regu- oculomotor neurones from mouse death. Proc. Natl. Acad. Sci. U.S.A. tive oxygen species produced in lation of alpha-amino-3-hydroxy-5- that are particularly resistant dur- 102, 12230–12235. motor neurons. J. Neurosci. 23, methyl-4-isoxazole-propionic acid ing amyotrophic lateral sclerosis Ogoshi, F., and Weiss, J. H. (2003). 2627–2633. receptor subunit expression in fore- (ALS)-related motoneurone disease. Heterogeneity of Ca2+-permeable Reynolds, I. J., and Hastings, T. G. brain and relationship to regional J. Physiol. 525(Pt 2), 433–445. AMPA/kainate channel expres- (1995). Glutamate induces the pro- susceptibility to hypoxic/ischemic Weiss, J. H., and Choi, D. W. (1991). sion in hippocampal pyramidal duction of reactive oxygen species injury. II. Human cerebral white Slow non-NMDA receptor medi- neurons: fluorescence imag- in cultured forebrain neurons fol- matter and cortex. J. Comp. Neurol. ated neurotoxicity and amyotrophic ing and immunocytochemical lowing NMDA receptor activation. 497, 61–77. lateral sclerosis. Adv. Neurol. 56, assessment. J. Neurosci. 23, J. Neurosci. 15, 3318–3327. Talos, D. M., Fishman, R. E., Park, 311–318. 10521–10530. Rossor, M. N., Emson, P. C., Moun- H., Folkerth, R. D., Follett, P. Weiss, J. H., Koh, J., Baimbridge, K. G., Ogoshi, F., Yin, H. Z., Kuppumbatti, Y., tjoy, C. Q., Roth, M., and Iversen, L., Volpe, J. J., and Jensen, F. and Choi, D. W. (1990). Cortical Song, B., Amindari, S., and Weiss, J. L. L. (1980). Reduced amounts of E. (2006b). Developmental regula- neurons containing somatostatin- or H. (2005). Tumor necrosis-factor- immunoreactive somatostatin in the tion of alpha-amino-3-hydroxy-5- parvalbumin-like immunoreactivity alpha (TNF-alpha) induces rapid temporal cortex in senile dementia methyl-4-isoxazole-propionic acid are atypically vulnerable to excito- insertion of Ca2+-permeable of Alzheimer type. Neurosci. Lett. 20, receptor subunit expression in fore- toxic injury in vitro. Neurology 40, alpha-amino-3-hydroxyl-5- 373–377. brain and relationship to regional 1288–1292. methyl-4-isoxazole-propionate Rothstein, J. D., Jin, L., Dykes-Hoberg, susceptibility to hypoxic/ischemic Weiss, J. H., Koh, J. Y., and Choi, D. (AMPA)/kainate (Ca-A/K) channels M.,and Kuncl,R.W.(1993). Chronic injury. I. Rodent cerebral white mat- W. (1989). Neurotoxicity of beta- in a subset of hippocampal pyra- inhibition of glutamate uptake pro- ter and cortex. J. Comp. Neurol. 497, N -methylamino-l-alanine (BMAA) midal neurons. Exp. Neurol. 193, duces a model of slow neurotoxic- 42–60. and beta-N -oxalylamino-l-alanine 384–393. ity. Proc. Natl. Acad. Sci. U.S.A. 90, Tateno, M., Sadakata, H., Tanaka, (BOAA) on cultured cortical neu- Opitz, T., Grooms, S. Y., Bennett, M. V., 6591–6595. M., Itohara, S., Shin, R. M., rons. Brain Res. 497, 64–71. and Zukin, R. S. (2000). Remodeling Sensi, S. L., Paoletti, P., Bush, A. I., and Miura, M., Masuda, M., Aosaki, Weiss, J. H., Yin, H. Z., and Choi, D. W. of alpha-amino-3-hydroxy-5- Sekler, I. (2009). Zinc in the physiol- T., Urushitani, M., Misawa, H., (1994). Basal forebrain cholinergic methyl-4-isoxazole-propionic ogy and pathology of the CNS. Nat. and Takahashi, R. (2004). Calcium- neurons are selectively vulnerable to acid receptor subunit compo- Rev. Neurosci. 10, 780–791. permeable AMPA receptors promote AMPA/kainate receptor-mediated sition in hippocampal neurons Sensi, S. L., Yin, H. Z., Carriedo, S. G., misfolding of mutant SOD1 protein neurotoxicity. Neuroscience 60, after global ischemia. Proc. Rao, S. S., and Weiss, J. H. (1999). and development of amyotrophic 659–664. Natl. Acad. Sci. U.S.A. 97, Preferential Zn2+ influx through lateral sclerosis in a transgenic Whitehouse, P. J., Price, D. L., Struble, 13360–13365. Ca2+-permeable AMPA/kainate mouse model. Hum. Mol. Genet. 13, R. G., Clark, A. W., Coyle, J. T., and Paoletti, P., Vergnano, A. M., Barbour, channels triggers prolonged mito- 2183–2196. Delon, M. R. (1982). Alzheimer’s B., and Casado, M. (2009). Zinc chondrial superoxide production. Teitelbaum, J. S., Zatorre, R. J., Car- disease and senile dementia: loss at glutamatergic synapses. Neuro- Proc. Natl. Acad. Sci. U.S.A. 96, penter, S., Gendron, D., Evans, of neurons in the basal forebrain. science 158, 126–136. 2414–2419. A. C., Gjedde, A., and Cashman, Science 215, 1237–1239. Pellegrini-Giampietro, D. E., Gorter, Shuttleworth, C. W., and Weiss, J. H. N. R. (1990) Neurologic seque- Yin, H., Turetsky, D., Choi, D. W., J. A., Bennett, M. V., and Zukin, (2011). Zinc: new clues to diverse lae of domoic acid intoxication and Weiss, J. H. (1994a). Corti- R. S. (1997). The GluR2 (GluR-B) roles in brain ischemia. Trends Phar- due to the ingestion of contami- cal neurones with Ca2+ permeable hypothesis: Ca(2+)-permeable macol. Sci. 32, 480–486. nated mussels. N.Engl.J.Med.322, AMPA/kainate channels display dis- AMPA receptors in neurological Spaethling, J. M., Klein, D. M., Singh, P., 1781–1787. tinct receptor immunoreactivity and disorders. Trends Neurosci. 20, and Meaney, D. F. (2008). Calcium- Tonder, N., Johansen, F. F., Frederick- are GABAergic. Neurobiol. Dis. 1, 464–470. permeable AMPA receptors appear son, C. J., Zimmer, J., and Diemer, 43–49. Peng, P.L., Zhong, X., Tu,W.,Soundara- in cortical neurons after traumatic N. H. (1990). Possible role of zinc in Yin,H. Z.,Lindsay,A. D.,and Weiss,J. H. pandian, M. M., Molner, P., Zhu, mechanical injury and contribute to the selective degeneration of dentate (1994b). Kainate injury to cultured D., Lau, L., Liu, S., Liu, F., and Lu, neuronal fate. J. Neurotrauma 25, hilar neurons after cerebral ischemia basal forebrain cholinergic neurons Y. (2006). ADAR2-dependent RNA 1207–1216. in the adult rat. Neurosci. Lett. 109, is Ca2+ dependent. Neuroreport 5, editing of AMPA receptor subunit Spencer, P. S., Nunn, P. B., Hugon, J., 247–252. 1477–1480. GluR2 determines vulnerability of Ludolph, A. C., Ross, S. M., Roy, Van Damme, P., Braeken, D., Calle- Yin, H. Z., Sensi, S. L., Carriedo, neurons in forebrain ischemia. Neu- D. N., and Robertson, R. C. (1987). waert, G., Robberecht, W., and Van S. G., and Weiss, J. H. (1999). ron 49, 719–733. Guam amyotrophic lateral sclerosis- Den Bosch, L. (2005). GluR2 defi- Dendritic localization of Ca(2+)- Qian, J., and Noebels, J. L. (2005). parkinsonism-dementia linked to a ciency accelerates motor neuron permeable AMPA/kainate channels Visualization of transmitter release plant excitant neurotoxin. Science degeneration in a mouse model in hippocampal pyramidal with zinc fluorescence detection at 237, 517–522. of amyotrophic lateral sclerosis. neurons. J. Comp. Neurol. 409, the mouse hippocampal mossy fibre Spencer, P. S., Roy, D. N., Ludolph, J. Neuropathol. Exp. Neurol. 64, 250–260. synapse. J. Physiol. 566, 747–758. A., Hugon, J., Dwivedi, M. P., and 605–612. Yin, H. Z., Sensi, S. L., Ogoshi, Rao, S. D., Banack, S. A., Cox, Schaumburg, H. H. (1986). Lath- Van Den Bosch, L., Vandenberghe, W., F., and Weiss, J. H. (2002). P. A., and Weiss, J. H. (2006). yrism: evidence for role of the Klaassen, H., Van Houtte, E., and Blockade of Ca2+-permeable BMAA selectively injures motor neuroexcitatory aminoacid BOAA. Robberecht, W. (2000). Ca(2+)- AMPA/kainate channels decreases neurons via AMPA/kainate recep- Lancet 2, 1066–1067. permeable AMPA receptors and oxygen-glucose deprivation- tor activation. Exp. Neurol. 201, Stellwagen, D., Beattie, E. C., Seo, J. Y., selective vulnerability of motor neu- induced Zn2+ accumulation and 244–252. and Malenka, R. C. (2005). Differen- rons. J. Neurol. Sci. 180, 29–34. neuronal loss in hippocampal Rao, S. D., and Weiss, J. H. (2004). tial regulation of AMPAreceptor and Vandenberghe, W., Robberecht, W., and pyramidal neurons. J. Neurosci. 22, Excitotoxic and oxidative cross-talk GABA receptor trafficking by tumor Brorson,J. R. (2000).AMPAreceptor 1273–1279.

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 6 Weiss Ca-AMPA channels in CNS disease

Yin, H. Z., Tang, D. T., and Weiss, J. permeable AMPA/kainate that could be construed as a potential the nervous system. Front. Mol. Neurosci. H. (2007). Intrathecal infusion of channels and triggers selective conflict of interest. 4:42. doi: 10.3389/fnmol.2011.00042 a Ca(2+)-permeable AMPA chan- neural injury. Neuroreport 6, Copyright © 2011 Weiss. This is an open- nel blocker slows loss of both motor 2553–2556. access article subject to a non-exclusive neurons and of the astrocyte gluta- Received: 31 August 2011; paper pending license between the authors and Frontiers mate transporter, GLT-1 in a mutant published: 23 September 2011; accepted: Media SA, which permits use, distribu- SOD1 rat model of ALS. Exp. Neurol. Conflict of Interest Statement: The 27 October 2011; published online: 14 tion and reproduction in other forums, 207, 177–185. author declares that the research was November 2011. provided the original authors and source Yin, H. Z., and Weiss, J. H. (1995). conducted in the absence of any Citation: Weiss JH (2011) Ca2+ are credited and other Frontiers condi- Zn(2+) permeates Ca(2+) commercial or financial relationships permeable AMPA channels in diseases of tions are complied with.

Frontiers in Molecular Neuroscience www.frontiersin.org November 2011 | Volume 4 | Article 42 | 7