Abstract
The invention of centrally active, positive modulators of AMPA-type glutamate receptors (“ampakines”) was prompted by the expectation that enhancing monosynaptic, fast excitatory post synaptic currents (EPSCs) would increase throughput in cortical networks and lower the threshold for induction of long-term potentiation (LTP), two events that could potentially enhance memory and cognition. Preclinical work has largely confirmed these various predictions and a small set of reports describe positive effects in humans. Later work raised the possibility that ampakines might have somewhat broader applications, a list that now extends from respiratory distress through autism, ADHD, depression, and schizophrenia. We here describe two general hypotheses to explain why ampakines might have therapeutic value with regard to disparate psychiatric illnesses. The first of these begins with the late nineteenth century idea that the cortex, in addition to its more traditionally understood functions, serves to regulate disturbances in lower brain systems. A version of this argument emerged in the 1950s as part of the intense research that followed on the discovery of links between the reticular formation in generating EEG and behavioral arousal. Various groups obtained evidence of a reticular–frontal cortical “loop” that served to modulate behavioral/physiological excitability. More recently, Carlsson and Carlsson expanded the loop concept to include brainstem biogenic amines; their model makes the explicit prediction that enhancing descending glutamatergic projections can be used to offset abnormal activity in the ascending dopaminergic system. Collectively, these theoretical positions point to the conclusion that positive modulation of cortical AMPA receptors should acutely reduce symptomology in disorders involving norepinephrine, dopamine, and serotonin. In accord with this assumption, ampakines depress high levels of arousal, counteract the effects of stimulants, and correct behavioral abnormalities in animal models of schizophrenia, ADHD, and depression. Work on humans is limited although recent evidence points to clinically meaningful improvements in ADHD. The second hypothesis grows out of two literatures, one defining the machinery that reorganizes the spine cytoskeleton so as to encode memory and the other suggesting that defects in these same cellular processes contribute to a surprisingly large number of disorders involving memory and cognition. With regard to the present chapter, these observations are united by the discovery that a potent regulator of cytoskeleton reorganization (Brain-Derived Neurotrophic Factor: BDNF) is up-regulated by ampakines. The possibility thus arises that daily treatments with the drugs could be used to drive structural changes otherwise blocked by any of several genetic or behavioral conditions. Tests of this argument have so far been limited to animal models but the results are encouraging. Daily treatments with a short half-life ampakine that increases cortical BDNF concentrations restored synaptic plasticity in middle-aged rats and in mice carrying the Huntington’s disease mutation. In the latter case, normalization of structural and physiological plasticity was accompanied by marked improvements in learning. Collectively, the results subsumed under the two hypotheses have to be viewed as remarkable: a class of drugs that has a single biophysical target produces positive changes of unprecedented breadth. But ampakines are still a recent invention arising from ideas in basic neuroscience. Whether the observed effects in animals actually relate to the two hypotheses remains to be formally tested and, above all else, there stands the absence of data from extensive clinical trials.
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References
Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307:462–465
Nicoll RA (2003) Expression mechanisms underlying long-term potentiation: a postsynaptic view. Philos Trans R Soc Lond B Biol Sci 358:721–726
Lynch G (1998) Memory and the brain: unexpected chemistries and a new pharmacology. Neurobiol Learn Mem 70:82–100
Abraham WC, Williams JM (2003) Properties and mechanisms of LTP maintenance. Neuroscientist 9:463–474
Gall CM, Lauterborn JC (2000) Regulation of BDNF expression: multifaceted, region-specific control of a neuronal survival factor in the adult CNS. In: Mocchetti I (ed) Neurobiology of the neurotrophins. FP Graham Publishing Co., Johnson City, TN, pp 541–579
Castren E, Berninger B, Leingartner A, Lindholm D (1998) Regulation of brain derived neurotrophic factor mRNA levels in hippocampus by neuronal activity. Prog Brain Res 117:57–64
Staubli U, Rogers G, Lynch G (1994) Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci USA 91:777–781
Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Centrally active modulators of glutamate (AMPA) receptors facilitate the induction of LTP in vivo. Proc Natl Acad Sci USA 91:11158–11162
Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM (2005) Mechanism of positive allosteric modulators acting on AMPA receptors. J Neurosci 25:9027–9036
Arai AC, Kessler M (2007) Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. Curr Drug Targets 8:583–602
Lynch G, Gall CM (2006) Ampakines and the threefold path to cognitive enhancement. Trends Neurosci 29:554–562
Lynch G (2006) Glutamate-based therapeutic approaches: ampakines. Curr Opin Pharmacol 6:82–88
Lynch G, Rex CS, Chen LY, Gall CM (2008) The substrates of memory: defects, treatments, and enhancement. Eur J Pharmacol 585:2–13
O’Neill MJ, Witkin JM (2007) AMPA receptor potentiators: application for depression and Parkinson’s disease. Curr Drug Targets 8:603–620
Ryder JW, Falcone JF, Manro JR, Svensson KA, Merchant KM (2006) Pharmacological characterization of cGMP regulation by the biarylpropylsulfonamide class of positive, allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. J Pharmacol Exp Ther 319:293–298
Sirvio J, Larson J, Quach CN, Rogers GA, Lynch G (1996) Effects of pharmacologically facilitating glutamatergic transmission in the trisynaptic intrahippocampal circuit. Neuroscience 74:1025–1035
Arai A, Kessler M, Rogers G, Lynch G (1996) Effects of a memory enhancing drug on AMPA receptor currents and synaptic transmission in hippocampus. J Pharmacol Exp Ther 278:627–638
Granger R, Staubli U, Davis M, Perez Y, Nilsson L, Rogers GA, Lynch G (1993) A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning-dependent task. Synapse 15:326–329
Larson J, Lieu T, Petchpradub V, LeDuc B, Ngo H, Rogers GA, Lynch G (1995) Facilitation of olfactory learning by a modulator of AMPA receptors. J Neurosci 15:8023–8030
Rogan MT, Staubli UV, LeDoux JE (1997) AMPA receptor facilitation accelerates fear learning without altering the level of conditioned fear acquired. J Neurosci 17:5928–5935
Ingvar M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Enhancement by an ampakine of memory encoding in humans. Exp Neurol 146:553–559
Ren J, Ding X, Funk GD, Greer JJ (2009) Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats. Anesthesiology 110:1364–1370
Ren J, Poon BY, Tang Y, Funk GD, Greer JJ (2006) Ampakines alleviate respiratory depression in rats. Am J Respir Crit Care Med 174:1384–1391
Greer JJ, Ren J (2009) Ampakine therapy to counter fentanyl-induced respiratory depression. Respir Physiol Neurobiol 168:153–157
Ogier M, Wang H, Hong E, Wang Q, Greenberg ME, Katz DM (2007) Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome. J Neurosci 27:10912–10917
Lynch G, Kramar EA, Rex CS, Jia Y, Chappas D, Gall CM, Simmons DA (2007) Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J Neurosci 27:4424–4434
Simmons DA, Rex CS, Palmer L, Pandyarajan V, Fedulov V, Gall CM, Lynch G (2009) Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington’s disease knockin mice. Proc Natl Acad Sci USA 106:4906–4911
Jourdi H, Hamo L, Oka T, Seegan A, Baudry M (2009) BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP(+)-induced toxicity in cultured hippocampal and mesencephalic slices. Neuropharmacology 56:876–885
O’Neill MJ, Murray TK, Whalley K, Ward MA, Hicks CA, Woodhouse S, Osborne DJ, Skolnick P (2004) Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson’s disease. Eur J Pharmacol 486:163–174
Hess U, Whalen S, Sandoval L, Lynch G, Gall C (2003) Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion. Neuroscience 121:509–521
York G, Steinberg D (2006) An introduction to the life and work of John Hughlings Jackson with a catalogue raisonné of his writings. Med Hist Suppl 26:3–157
Dell P (1963) Reticular homeostasis and critical reactivity. In: Moruzzi G, Fessard A, Jasper H (eds) Brain mechanisms. Elsevier, New York, pp 82–103
Bonvallet M, Hugelin A (1961) Influence de la formation reticulaire et du cortex cerebral sur l’excitabilite motrice au cours de Phypoxie. Electroencephalogr Clin Neurophysiol 13:270–284
Hugelin A, Bonvallet M, Dell P (1959) Activation reticulaire et corticale d’origine chemoceptive au cours Phypoxie. Electroencephalogr Clin Neurophysiol 11:325–340
Groves PM, Wilson CJ, Boyle RD (1974) Brain stem pathways, cortical modulation, and habituation of the acoustic startle response. Behav Biol 10:391–418
Fahn S (2008) The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord 23(Suppl 3):S497–S508
Anden NE, Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA, Larsson K (1964) Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci 3:523–530
Lynch G, Smith RL, Robertson R (1973) Direct projections from brainstem to telencephalon. Exp Brain Res 17:221–228
Steriade M (1996) Arousal: revisiting the reticular activating system. Science 272:225–226
Lynch GS, Ballantine P 2nd, Campbell BA (1969) Potentiation of behavioral arousal after cortical damage and subsequent recovery. Exp Neurol 23:195–206
Carlsson M, Carlsson A (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia – implications for schizophrenia and Parkinson’s disease. Trends Neurosci 13:272–276
Carlsson A, Hansson LO, Waters N, Carlsson ML (1999) A glutamatergic deficiency model of schizophrenia. Br J Psychiatry Suppl 37:2–6
Carlsson A (1995) Neurocircuitries and neurotransmitter interactions in schizophrenia. Int Clin Psychopharmacol 10(Suppl 3):21–28
Carlsson A (2006) The neurochemical circuitry of schizophrenia. Pharmacopsychiatry 39(Suppl 1):S10–S14
Purpura D (1975) Normal and aberrant neuronal development in the cerebral cortex of human fetus and young infant. UCLA Forum Med Sci 18:141–169
Irwin S, Patel B, Idupulapati M, Harris J, Crisostomo R, Larsen B, Kooy F, Willems P, Cras P, Kozlowski P et al (2001) Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet 98:161–167
Rudelli R, Brown W, Wisniewski K, Jenkins E, Laure-Kamionowska M, Connell F, Wisniewski H (1985) Adult fragile X syndrome. Clinico-neuropathologic findings. Acta Neuropathol 67:289–295
Wisniewski K, Segan S, Miezejeski C, Sersen E, Rudelli R (1991) The Fra(X) syndrome: neurological, electrophysiological, and neuropathological abnormalities. Am J Med Genet 38:476–480
Marin-Padilla M (1976) Pyramidal cell abnormalities in the motor cortex of a child with Down’s syndrome. A Golgi study. J Comp Neurol 167:63–81
Zhou Z, Hong E, Cohen S, Zhao W, Ho H, Schmidt L, Chen W, Lin Y, Savner E, Griffith E et al (2006) Brain-specific phosphorylation of MeCP2 regulates activity-dependent BDNF transcription, dendritic growth, and spine maturation. Neuron 52:255–269
Kaufmann WE, Moser HW (2000) Dendritic anomalies in disorders associated with mental retardation. Cereb Cortex 10:981–991
Chechlacz M, Gleeson JG (2003) Is mental retardation a defect of synapse structure and function? Pediatr Neurol 29:11–17
van Galen EJ, Ramakers GJ (2005) Rho proteins, mental retardation and the neurobiological basis of intelligence. Prog Brain Res 147:295–317
Ramakers G (2002) Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 25:191–199
Node-Langlois R, Muller D, Boda B (2006) Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Sci 119:4986–4993
Govek E, Newey S, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1–49
Chen LY, Rex CS, Casale MS, Gall CM, Lynch G (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci 27:5363–5372
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017–3029
Chen LY, Rex CS, Sanaiha Y, Lynch G, Gall CM (2010) Learning induces neurotrophin signaling at hippocampal synapses. Proc Natl Acad Sci USA 107(15):7030–7035
Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM, Lynch G (2009) Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol 186:85–97
Kramár EA, Chen LY, Brandon NJ, Rex CS, Liu F, Gall CM, Lynch G (2009) Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity. J Neurosci 29:12982–12993
Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM (2000) Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 20:8–21
Legutko B, Li X, Skolnick P (2001) Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator. Neuropharmacology 40:1019–1027
Larson J, Quach CN, LeDuc B, Nguyen A, Rogers GA, Lynch G (1996) Effects of an AMPA receptor modulator on methamphetamine-induced hyperactivity in rats. Brain Res 738:353–356
Johnson S, Luu N, Herbst T, Knapp R, Lutz D, Arai A, Rogers G, Lynch G (1999) Synergistic interactions between ampakines and antipsychotic drugs. J Pharmacol Exp Ther 289:392–397
Davis CM, Moskovitz B, Nguyen MA, Arai A, Lynch G, Granger R (1997) A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors. Psychopharmacology 133:161–167
Gainetdinov RR, Mohn AR, Bohn LM, Caron MG (2001) Glutamatergic modulation of hyperactivity in mice lacking dopamine transporter. Proc Natl Acad Sci USA 98:11047–11054
Lipina T, Weiss K, Roder J (2007) The ampakine CX546 restores the prepulse inhibition and latent inhibition deficits in mGluR5-deficient mice. Neuropsychopharmacology 32:745–756
Ungerstedt U (1976) 6-Hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway: the turning syndrome. Pharmacol Ther 2:37–40
Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand 367:69–93
Broberg B, Glenthøj B, Dias R, Larsen D, Olsen C (2009) Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia–sub-chronic and early postnatal PCP treatment in attentional set-shifting. Psychopharmacology (Berl) 206:631–640
Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 70:187–192
Li X, Tizzano J, Griffey K, Clay M, Lindstrom T, Skolnick P (2001) Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 40:1028–1033
Li X, Witkin J, Need A, Skolnick P (2003) Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol 23:419–430
Knapp R, Goldenberg R, Shuck C, Cecil A, Watkins J, Miller C, Crites G, Malatynska E (2002) Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol 440:27–35
Palmer LC, Hess US, Larson J, Rogers GA, Gall CM, Lynch G (1997) Comparison of the effects of an ampakine with those of methamphetamine on aggregate neuronal activity in cortex versus striatum. Mol Brain Res 46:127–135
Porrino L, Daunais J, Rogers G, Hampson R, Deadwyler S (2005) Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol 3:e299
Vonsattel J, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384
Lawrence A, Hodges J, Rosser A, Kershaw A, French-Constant C, Rubinsztein D, Robbins T, Sahakian B (1998) Evidence for specific cognitive deficits in preclinical Huntington’s disease. Brain Pathol 121:1329–1341
Kirkwood S, Siemers E, Hodes M, Conneally P, Christian J, Foroud T (2000) Subtle changes among presymptomatic carriers of the Huntington’s disease gene. J Neurol Neurosurg Psychiatry 69:773–779
Hodgson J, Agopyan N, Gutekunst C, Leavitt B, LePiane F, Singaraja R, Smith D, Bissada N, McCutcheon K, Nasir J et al (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:181–192
Usdin MT, Shelbourne PF, Myers RM, Madison DV (1999) Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet 8:839–846
Murphy KP, Carter RJ, Lione LA, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (2000) Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J Neurosci 20:5115–5123
Zuccato C, Cattaneo E (2007) Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 81:294–330
Lauterborn J, Troung G, Baudry M, Bi X, Lynch G, Gall C (2003) Chronic elevation of brain-derived neurotrophic factor by ampakines. J Pharmacol Exp Ther 307:297–305
Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM (2009) Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression. Neuroscience 159:283–295
Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM, Lynch G (2007) Evidence that long-term potentiation occurs within individual hippocampal synapses during learning. J Neurosci 27:8031–8039
Park D, Lautenschlager G, Hedden T, Davidson N, Smith A, Smith P (2002) Models of visuospatial and verbal memory across the adult life span. Psychol Aging 17:299–320
Deupree DL, Bradley J, Turner DA (1993) Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol Aging 14:249–258
Herndon JG, Moss MB, Rosene DL, Killiany RJ (1997) Patterns of cognitive decline in aged rhesus monkeys. Behav Brain Res 87:25–34
Rex C, Kramar E, Colgin L, Lin B, Gall C, Lynch G (2005) Long-term potentiation is impaired in middle-aged rats: regional specificity and reversal by adenosine receptor antagonists. J Neurosci 25:5956–5966
Rex CS, Lauterborn JC, Lin CY, Kramar EA, Rogers GA, Gall CM, Lynch G (2006) Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor. J Neurophysiol 96:677–685
Cunha R, Almeida T, Ribeiro J (2001) Parallel modification of adenosine extracellular metabolism and modulatory action in the hippocampus of aged rats. J Neurochem 76:372–382
Phillips S, Sherwin B (1993) Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 17:485–495
Devi G, Hahn K, Massimi S, Zhivotovskaya E (2005) Prevalence of memory loss complaints and other symptoms associated with the menopause transition: a community survey. Gend Med 2:255–264
Hachul H, Bittencourt L, Soares JJ, Tufik S, Baracat E (2009) Sleep in post-menopausal women: differences between early and late post-menopause. Eur J Obstet Gynecol Reprod Biol 145:81–84
Weber M, Mapstone M (2009) Memory complaints and memory performance in the menopausal transition. Menopause 16:694–700
Hojo Y, Murakami G, Mukai H, Higo S, Hatanaka Y, Ogiue-Ikeda M, Ishii H, Kimoto T, Kawato S (2008) Estrogen synthesis in the brain – role in synaptic plasticity and memory. Mol Cell Endocrinol 290:31–43
Kramar EA, Chen LY, Lauterborn JC, Simmons DA, Gall CM, Lynch G BDNF and BDNF up-regulation rescue synaptic plasticity in ovariectomized rats (Submitted)
Comery T, Harris J, Willems P, Oostra B, Irwin S, Weiler I, Greenough W (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci USA 94:5401–5404
Irwin S, Idupulapati M, Gilbert M, Harris J, Chakravarti A, Rogers E, Crisostomo R, Larsen B, Mehta A, Alacantara C et al (2002) Dendritic spine and dendritic field characteristics on layer V pyramidal neurons in the visual cortex of fragile-X knockout mice. Am J Med Genet 111:140–146
Purpura DP (1974) Dendritic spine “dysgenesis” and mental retardation. Science 186:1126–1128
Dindot S, Antalffy B, Bhattacharjee M, Beaudet A (2008) The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 17:111–118
Penagarikano O, Mulle J, Warren S (2007) The pathophysiology of fragile x syndrome. Annu Rev Genomics Hum Genet 8:109–129
Dictenberg J, Swanger S, Antar L, Singer R, Bassell G (2008) A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev Cell 14:926–939
Davidovic L, Jaglin XH, Lepagnol-Bestel AM, Tremblay S, Simonneau M, Bardoni B, Khandjian EW (2007) The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules. Hum Mol Genet 16:3047–3058
Ling S, Fahrner P, Greenough W, Gelfand V (2004) Transport of Drosophila fragile X mental retardation protein-containing ribonucleoprotein granules by kinesin-1 and cytoplasmic dynein. Proc Natl Acad Sci USA 101:17428–17433
Ohashi S, Koike K, Omori A, Ichinose S, Ohara S, Kobayashi S, Sato TA, Anzai K (2002) Identification of mRNA/protein (mRNP) complexes containing Puralpha, mStaufen, fragile X protein, and myosin Va and their association with rough endoplasmic reticulum equipped with a kinesin motor. J Biol Chem 277:37804–37810
Lauterborn JC, Rex CS, Kramar E, Chen LY, Pandyarajan V, Lynch G, Gall CM (2007) Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 27:10685–10694
Meredith RM, Holmgren CD, Weidum M, Burnashev N, Mansvelder HD (2007) Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking fragile X gene FMR1. Neuron 54:627–638
Larson J, Jessen R, Kim D, Fine A, du Hoffmann J (2005) Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein. J Neurosci 25:9460–9469
Li J, Pelletier MR, Perez Velazquez JL, Carlen PL (2002) Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol Cell Neurosci 19:138–151
Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, Chattarji S, Tonegawa S (2007) Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci USA 104:11489–11494
Zhao M, Toyoda H, Ko S, Ding H, Wu L, Zhuo M (2005) Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J Neurosci 25:7385–7392
Bozdagi O, Rich E, Tronel S, Sadahiro M, Patterson K, Shapiro ML, Alberini CM, Huntley GW, Salton SR (2008) The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J Neurosci 28:9857–9869
Marty S, da Penha BM, Berninger B (1997) Neurotrophins and activity-dependent plasticity of cortical interneurons. Trends Neurosci 20:202
Kramar EA, Lin B, Rex CS, Gall CM, Lynch G (2006) Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci USA 103:5579–5584
Wang XB, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, Huntley GW (2008) Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci USA 105:19520–19525
Kramar EA, Chen LY, Brandon NJ, Rex CS, Liu F, Gall CM, Lynch G (2009) Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity. J Neurosci 29:12982–12993
Chen LY, Rex CS, Babayan AH, Kramar EK, Lynch G, Gall CM, Lauterborn JC (2010) Physiological activation of synaptic Rac > PAK signaling is defective in a mouse model of fragile-X syndrome. J Neurosci (in press)
Acknowledgments
Research described in this commentary was supported by National Institutes of Neurological Disorders and Stoke grants NS45260 and NS051823 to G.L. and C.M.G. and National Institutes of Mental Health grant MH083346 to C.M.G. and J.C.L.
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Lynch, G., Lauterborn, J.C., Gall, C.M. (2010). Positive Modulation of AMPA Receptors as a Broad-Spectrum Strategy for Treating Neuropsychiatric Disorders. In: Skolnick, P. (eds) Glutamate-based Therapies for Psychiatric Disorders. Milestones in Drug Therapy. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0346-0241-9_5
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