Abstract
N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in the pathophysiology of schizophrenia. New glutamatergic mechanisms involving metabotropic receptors have been recently proposed to further expand this hypothesis. “Homer” is a family of postsynaptic density proteins functionally and physically attached to glutamate metabotropic receptors. We investigated the activation of the early gene form of Homer after acute treatment with typical or atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This activation was compared with that of c-fos, considered a putative molecular marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15 mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were sacrificed ninety minutes after injection and the brains were processed for quantitative in situ hybridization histochemistry. Haloperidol induced a statistically significant increase of Homer both in caudate-putamen and nucleus accumbens compared with controls; clozapine induced Homer significantly only in the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced increase of Homer expression in caudate-putamen and nucleus accumbens and attenuated the clozapine-induced increase in the accumbens. The c-fos gene expression was potently induced by haloperidol in caudate-putamen and nucleus accumbens, and by clozapine only in the accumbens. The adjunction of D-cycloserine enhanced c-fos expression only for clozapine in both regions of the forebrain. These results demonstrate a differential involvement of glutamatergic metabotropic system in gene expression modulation induced by typical or atypical antipsychotic drugs and may suggest new molecular basis for the augmentation strategy by a glycine site partial agonist.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Andersen JM, Lindberg V, Myhrer T . ( 2002 ): Effects of scopolamine and D-cycloserine on non-spatial reference memory in rats . Behav Brain Res 129 : 211 – 216
Austin MC, Schultzberg M, Abbott LC, Montpied P, Evers JR, Paul SM, Crawley JN . ( 1992 ): Expression of tyrosine hydroxylase in cerebellar Purkinje neurons of the mutant tottering and leaner mouse . Brain Res Mol Brain Res 15 : 227 – 240
Baran H, Gramer M, Loscher W . ( 1995 ): Alterations in plasma and brain amino acids after administration of the glycine/NMDA receptor partial agonist, D-cycloserine, to mice and rats . Eur J Pharmacol 273 : 197 – 201
Brakeman PR, Lanahan AA, O′Brien R, Roche K, Barnes CA, Huganir RL, Worley PF . ( 1997 ): Homer: a protein that selectively binds metabotropic glutamate receptors . Nature 386 : 284 – 288
Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L, Malhotra AK, Pickar D . ( 1998 ): Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach . Synapse 29 : 142 – 147
Cascella NG, Macciardi F, Cavallini C, Smeraldi E . ( 1994 ): d-cycloserine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label study . J Neural Transm Gen Sect 95 : 105 – 111
Curran T, Gordon MB, Rubino KL, Sambucetti LC . ( 1987 ): Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro . Oncogene 2 : 79 – 84
de Bartolomeis A, Aloj L, Ambesi-Impiombato A, Bravi D, Caraco C, Muscettola G, Barone P . ( 2002 ): Acute administration of antipsychotics modulates Homer striatal gene expression differentially . Brain Res Mol Brain Res 98 : 124 – 129
de Bartolomeis A, Austin MC, Goodwin GA, Spear LP, Pickar D, Crawley JN . ( 1994 ): Dopaminergic and peptidergic mRNA levels in juvenile rat brain after prenatal cocaine treatment . Brain Res Mol Brain Res 21 : 321 – 332
Depoortere R, Perrault G, Sanger DJ . ( 1999 ): Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various sites on the NMDA receptor complex . Behav Pharmacol 10 : 51 – 62
Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC . ( 2000 ): Placebo-controlled trial of glycine added to clozapine in schizophrenia . Am J Psychiatry 157 : 826 – 828
Goff DC, Henderson DC, Evins AE, Amico E . ( 1999a ): A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia . Biol Psychiatry 45 : 512 – 514
Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, McCarley R, Coyle JT . ( 1999b ): A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia . Arch Gen Psychiatry 56 : 21 – 27
Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT . ( 1996 ): D-cycloserine added to clozapine for patients with schizophrenia . Am J Psychiatry 153 : 1628 – 1630
Guo N, Klitenick MA, Tham CS, Fibiger HC . ( 1995 ): Receptor mechanisms mediating clozapine-induced c-fos expression in the forebrain . Neuroscience 65 : 747 – 756
Heresco-Levy U . ( 2000 ): N-Methyl-D-aspartate (NMDA) receptor-based treatment approaches in schizophrenia: the first decade . Int J Neuropsychopharmacol 3 : 243 – 258
Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D . ( 1996 ): Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia . Br J Psychiatry 169 : 610 – 617
Hiroi N, Graybiel AM . ( 1996 ): Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum . J Comp Neurol 374 : 70 – 83
Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP . ( 1994 ): Amelioration of negative symptoms in schizophrenia by glycine . Am J Psychiatry 151 : 1234 – 1236
Kato A, Ozawa F, Saitoh Y, Fukazawa Y, Sugiyama H, Inokuchi K . ( 1998 ): Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors . J Biol Chem 273 : 23969 – 23975
Loscher W, Wlaz P, Rundfeldt C, Baran H, Honack D . ( 1994 ): Anticonvulsant effects of the glycine/NMDA receptor ligands D- cycloserine and D-serine but not R-(+)-HA-966 in amygdala-kindled rats . Br J Pharmacol 112 : 97 – 106
MacGibbon GA, Lawlor PA, Bravo R, Dragunow M . ( 1994 ): Clozapine and haloperidol produce a differential pattern of immediate early gene expression in rat caudate-putamen, nucleus accumbens, lateral septum and islands of Calleja . Brain Res Mol Brain Res 23 : 21 – 32
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A . ( 1996 ): NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers . Neuropsychopharmacology 14 : 301 – 307
Merchant KM, Dorsa DM . ( 1993 ): Differential induction of neurotensin and c-fos gene expression by typical versus atypical antipsychotics . Proc Natl Acad Sci USA 90 : 3447 – 3451
Moghaddam B, Adams BW . ( 1998 ): Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats . Science 281 : 1349 – 1352
Monahan JB, Handelmann GE, Hood WF, Cordi AA . ( 1989 ): D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats . Pharmacol Biochem Behav 34 : 649 – 653
Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J, Weinberg RJ, Worley PF, Sheng M . ( 1999 ): Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin . Neuron 23 : 569 – 582
Olney JW, Newcomer JW, Farber NB . ( 1999 ): NMDA receptor hypofunction model of schizophrenia . J Psychiatr Res 33 : 523 – 533
Paxinos G, Watson C . ( 1986 ): The Rat Brain in Stereotaxic Coordinates, 2nd ed . New York, Academic Press
Robertson GS, Fibiger HC . ( 1992 ): Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine . Neuroscience 46 : 315 – 328
Robertson GS, Matsumura H, Fibiger HC . ( 1994 ): Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity . J Pharmacol Exp Ther 271 : 1058 – 1066
Semba J, Sakai MW, Suhara T, Akanuma N . ( 1999 ): Differential effects of acute and chronic treatment with typical and atypical neuroleptics on c-fos mRNA expression in rat forebrain regions using non-radioactive in situ hybridization . Neurochem Int 34 : 269 – 277
Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF . ( 1998 ): Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors . Neuron 21 : 717 – 726
van Berckel BN, Evenblij CN, van Loon BJ, Maas MF, van der Geld MA, Wynne HJ, van Ree JM, Kahn RS . ( 1999 ): D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study . Neuropsychopharmacology 21 : 203 – 210
Wlaz P, Baran H, Loscher W . ( 1994 ): Effect of the glycine/NMDA receptor partial agonist, D-cycloserine, on seizure threshold and some pharmacodynamic effects of MK-801 in mice . Eur J Pharmacol 257 : 217 – 225
Young WS 3rd, Bonner TI, Brann MR . ( 1986 ): Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain . Proc Natl Acad Sci USA 83 : 9827 – 9831
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Polese, D., de Serpis, A., Ambesi-Impiombato, A. et al. Homer 1a Gene Expression Modulation by Antipsychotic Drugs: Involvement of the Glutamate Metabotropic System and Effects of D-Cycloserine. Neuropsychopharmacol 27, 906–913 (2002). https://doi.org/10.1016/S0893-133X(02)00371-8
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(02)00371-8
Keywords
This article is cited by
-
Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq
Metabolic Brain Disease (2016)
-
Glutamatergic Postsynaptic Density Protein Dysfunctions in Synaptic Plasticity and Dendritic Spines Morphology: Relevance to Schizophrenia and Other Behavioral Disorders Pathophysiology, and Implications for Novel Therapeutic Approaches
Molecular Neurobiology (2014)
-
Calcium-Dependent Networks in Dopamine–Glutamate Interaction: The Role of Postsynaptic Scaffolding Proteins
Molecular Neurobiology (2012)
-
Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole
Psychopharmacology (2010)
-
Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia
European Archives of Psychiatry and Clinical Neuroscience (2009)
