Altered expression of schizophrenia-related genes in mice lacking mGlu5 receptors

Springer Science and Business Media LLC - Tập 268 - Trang 77-87 - 2016
Alessia Luoni1, Peter Gass2, Paolo Brambilla3, Mirella Ruggeri4, Marco A. Riva1, Dragos Inta2,5
1Department of Pharmacological and Biomolecular Sciences, Center of Neuropharmacology, Università degli Studi di Milano, Milan, Italy
2Department of Psychiatry and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
3Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
4Section of Psychiatry, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona, Italy
5Department of Psychiatry (UPK), University of Basel, Basel, Switzerland

Tóm tắt

The evidence underlying the so-called glutamatergic hypothesis ranges from NMDA receptor hypofunction to an imbalance between excitatory and inhibitory circuits in specific brain structures. Among all glutamatergic system components, metabotropic receptors play a main role in regulating neuronal excitability and synaptic plasticity. Here, we investigated, using qRT-PCR and western blot, consequences in the hippocampus and prefrontal/frontal cortex (PFC/FC) of mice with a genetic deletion of the metabotropic glutamate receptor 5 (mGlu5), addressing key components of the GABAergic and glutamatergic systems. We found that mGlu5 knockout (KO) mice showed a significant reduction of reelin, GAD65, GAD67 and parvalbumin mRNA levels, which is specific for the PFC/FC, and that is paralleled by a significant reduction of protein levels in male KO mice. We next analyzed the main NMDA and AMPA receptor subunits, namely GluN1, GluN2A, GluN2B and GluA1, and we found that mGlu5 deletion determined a significant reduction of their mRNA levels, also within the hippocampus, with differences between the two genders. Our data suggest that neurochemical abnormalities impinging the glutamatergic and GABAergic systems may be responsible for the behavioral phenotype associated with mGlu5 KO animals and point to the close interaction of these molecular players for the development of neuropsychiatric disorders such as schizophrenia. These data could contribute to a better understanding of the involvement of mGlu5 alterations in the molecular imbalance between excitation and inhibition underlying the emergence of a schizophrenic-like phenotype and to understand the potential of mGlu5 modulators in reversing the deficits characterizing the schizophrenic pathology.

Tài liệu tham khảo

Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG (2008) Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 60:358–403 Balu DT, Coyle JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35:848–870 Molteni R, Calabrese F, Racagni G, Fumagalli F, Riva MA (2009) Antipsychotic drug actions on gene modulation and signaling mechanisms. Pharmacol Ther 124:74–85 Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Rajagopal L, Harte MK (2010) Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on nmda receptor antagonism. Pharmacol Ther 128:419–432 Bubenikova-Valesova V, Horacek J, Vrajova M, Hoschl C (2008) Models of schizophrenia in humans and animals based on inhibition of nmda receptors. Neurosci Biobehav Rev 32:1014–1023 du Bois TM, Deng C, Han M, Newell KA, Huang XF (2009) Excitatory and inhibitory neurotransmission is chronically altered following perinatal nmda receptor blockade. Eur Neuropsychopharmacol 19:256–265 Lewis DA, Gonzalez-Burgos G (2006) Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12:1016–1022 Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376 Homayoun H, Moghaddam B (2007) Nmda receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500 Lewis DA, Curley AA, Glausier JR, Volk DW (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 35:57–67 Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4–15 Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322 Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041 Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate ca1 pyramidal cell function. J Neurosci 21:5925–5934 Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, Bernardi G, Calabresi P (2001) Metabotropic glutamate receptor 5 mediates the potentiation of n-methyl-d-aspartate responses in medium spiny striatal neurons. Neuroscience 106:579–587 Perroy J, Raynaud F, Homburger V, Rousset MC, Telley L, Bockaert J, Fagni L (2008) Direct interaction enables cross-talk between ionotropic and group i metabotropic glutamate receptors. J Biol Chem 283:6799–6805 Brody SA, Dulawa SC, Conquet F, Geyer MA (2004) Assessment of a prepulse inhibition deficit in a mutant mouse lacking mglu5 receptors. Mol Psychiatry 9:35–41 Brody SA, Conquet F, Geyer MA (2004) Effect of antipsychotic treatment on the prepulse inhibition deficit of mglur5 knockout mice. Psychopharmacology 172:187–195 Gray L, van den Buuse M, Scarr E, Dean B, Hannan AJ (2009) Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with n-methyl-d-aspartic acid receptor up-regulation. Int J Neuropsychopharmacol 12:45–60 Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156:117–154 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 Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM, Roder JC (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced ca1 long-term potentiation (ltp) but normal ca3 ltp. J Neurosci 17:5196–5205 Wijetunge LS, Till SM, Gillingwater TH, Ingham CA, Kind PC (2008) Mglur5 regulates glutamate-dependent development of the mouse somatosensory cortex. J Neurosci 28:13028–13037 Jia Z, Lu Y, Henderson J, Taverna F, Romano C, Abramow-Newerly W, Wojtowicz JM, Roder J (1998) Selective abolition of the nmda component of long-term potentiation in mice lacking mglur5. Learn Mem 5:331–343 Ridder S, Chourbaji S, Hellweg R, Urani A, Zacher C, Schmid W, Zink M, Hortnagl H, Flor H, Henn FA, Schutz G, Gass P (2005) Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. J Neurosci 25:6243–6250 Inta D, Monyer H, Sprengel R, Meyer-Lindenberg A, Gass P (2010) Mice with genetically altered glutamate receptors as models of schizophrenia: a comprehensive review. Neurosci Biobehav Rev 34:285–294 Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA 95:15718–15723 Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A, Caruncho HJ (1998) Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats. Proc Natl Acad Sci USA 95:3221–3226 Berretta S (2012) Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 62:1584–1597 Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW, Mirnics K, Lewis DA (2008) Alterations in gaba-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol psychiatry 13:147–161 Kawaguchi Y, Kubota Y (1997) Gabaergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb Cortex 7:476–486 Rudy B, Fishell G, Lee S, Hjerling-Leffler J (2011) Three groups of interneurons account for nearly 100% of neocortical gabaergic neurons. Dev Neurobiol 71:45–61 Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ, Conn PJ (2003) Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 306:116–123 Kotecha SA, MacDonald JF (2003) Signaling molecules and receptor transduction cascades that regulate nmda receptor-mediated synaptic transmission. Int Rev Neurobiol 54:51–106 Coyle JT, Tsai G, Goff D (2003) Converging evidence of nmda receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 1003:318–327 Gordon JA (2010) Testing the glutamate hypothesis of schizophrenia. Nat Neurosci 13:2–4 Kantrowitz JT, Javitt DC (2010) N-methyl-d-aspartate (nmda) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 83:108–121 Meador-Woodruff JH, Healy DJ (2000) Glutamate receptor expression in schizophrenic brain. Brain Res Brain Res Rev 31:288–294 Corti C, Xuereb JH, Crepaldi L, Corsi M, Michielin F, Ferraguti F (2011) Altered levels of glutamatergic receptors and Na+/k+ atpase-alpha1 in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 128:7–14 Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324 Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E, Akbarian S (2009) Molecular determinants of dysregulated gabaergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 65:1006–1014 Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E (2000) Decrease in reelin and glutamic acid decarboxylase67 (gad67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 57:1061–1069 Liu WS, Pesold C, Rodriguez MA, Carboni G, Auta J, Lacor P, Larson J, Condie BG, Guidotti A, Costa E (2001) Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc Natl Acad Sci USA 98:3477–3482 Campo CG, Sinagra M, Verrier D, Manzoni OJ, Chavis P (2009) Reelin secreted by gabaergic neurons regulates glutamate receptor homeostasis. PLoS One 4:e5505 Gonzalez-Burgos G, Fish KN, Lewis DA (2011) Gaba neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia. Neural Plast 2011:723184 Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45–56 Keefe RS, Fenton WS (2007) How should dsm-v criteria for schizophrenia include cognitive impairment? Schizophr Bull 33:912–920 Barnes SA, Pinto-Duarte A, Kappe A, Zembrzycki A, Metzler A, Mukamel EA, Lucero J, Wang X, Sejnowski TJ, Markou A, Behrens MM (2015) Disruption of mglur5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders. Mol psychiatry 20:1161–1172 Pietraszek M, Nagel J, Gravius A, Schafer D, Danysz W (2007) The role of group i metabotropic glutamate receptors in schizophrenia. Amino Acids 32:173–178 Olney JW, Farber NB (1995) Nmda antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology 13:335–345 Tamminga CA (1998) Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21–36 Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced nmda receptor expression display behaviors related to schizophrenia. Cell 98:427–436 Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal nmda receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83 Sprengel R (2006) Role of ampa receptors in synaptic plasticity. Cell Tissue Res 326:447–455 Kopec CD, Real E, Kessels HW, Malinow R (2007) Glur1 links structural and functional plasticity at excitatory synapses. J Neurosci 27:13706–13718 Inta D, Vogt MA, Elkin H, Weber T, Lima-Ojeda JM, Schneider M, Luoni A, Riva MA, Gertz K, Hellmann-Regen J, Kronenberg G, Meyer-Lindenberg A, Sprengel R, Gass P (2014) Phenotype of mice with inducible ablation of glua1 ampa receptors during late adolescence: relevance for mental disorders. Hippocampus 24:424–435 Wiedholz LM, Owens WA, Horton RE, Feyder M, Karlsson RM, Hefner K, Sprengel R, Celikel T, Daws LC, Holmes A (2008) Mice lacking the ampa glur1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors. Mol psychiatry 13:631–640 Bertani M, Lasalvia A, Bonetto C, Tosato S, Cristofalo D, Bissoli S, De Santi K, Mazzoncini R, Lazzarotto L, Santi M, Sale A, Scalabrin D, Abate M, Tansella M, Rugger M (2012) The influence of gender on clinical and social characteristics of patients at psychosis onset: a report from the Psychosis Incident Cohort Outcome Study (PICOS). Psychol Med 42:769–780 Matta JA, Ashby MC, Sanz-Clemente A, Roche KW, Isaac JT (2011) Mglur5 and nmda receptors drive the experience- and activity-dependent nmda receptor nr2b to nr2a subunit switch. Neuron 70:339–351 Sullivan EM, O’Donnell P (2012) Inhibitory interneurons, oxidative stress, and schizophrenia. Schizophr Bull 38:373–376 Timms AE, Dorschner MO, Wechsler J, Choi KY, Kirkwood R, Girirajan S, Baker C, Eichler EE, Korvatska O, Roche KW, Horwitz MS, Tsuang DW (2013) Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. JAMA Psychiatry 70:582–590 Matosin N, Fernandez-Enright F, Fung SJ, Lum JS, Engel M, Andrews JL, Huang XF, Weickert CS, Newell KA (2015) Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation. Acta Neuropathol 30:119–129 Iasevoli F, Tomasetti C, Buonaguro EF, de Bartolomeis A (2014) The glutamatergic aspects of schizophrenia molecular pathophysiology: role of the postsynaptic density, and implications for treatment. Curr Neuropharmacol 12:219–238 Garcia RA, Vasudevan K, Buonanno A (2000) The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc Natl Acad Sci USA 97:3596–3601 Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12:824–828 Conn PJ, Lindsley CW, Jones CK (2009) Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci 30:25–31 Balu DT, Li Y, Takagi S, Presti KT, Ramikie TS, Rook JM, Jones CK, Lindsley CW, Conn PJ, Bolshakov VY, Coyle JT (2016) An mglu5-positive allosteric modulator rescues the neuroplasticity deficits in a genetic model of nmda receptor hypofunction in schizophrenia. Neuropsychopharmacology 41:2052–2061 Inta D, Vogt MA, Luoni A, Filipovic D, Lima-Ojeda JM, Pfeiffer N, Gasparini F, Riva MA, Gass P (2013) Significant increase in anxiety during aging in mglu5 receptor knockout mice. Behav Brain Res 241:27–31