OJMP  Vol.3 No.3 , April 2014
Hypo-Anxious Phenotype of Adolescent Offspring Prenatally Exposed to LPS Is Associated with Reduced mGluR5 Expression in Hippocampus
Abstract: Many studies have reported long-term modulation of metabotropic glutamate receptor 5 (mGluR5) by inflammatory processes and a pharmacological modulation of mGluR5 is known to regulate anxiety level. However, it is not known if non-pharmacological modulation of mGluR5 by inflammation impaired the unconditional level of anxiety. In this study, we investigated this relation in LPS prenatal immune challenge (120 μg/kg, 3x i.p. injection in late gestation), a developmental model of neuroinflammation in which some studies have reported hypo-anxious phenotype. Using positron emission tomographic imaging (PET) approaches, we have demonstrated a decrease in the binding potential of [18F]fluoro-5-(2-pyridinylethynyl)benzonitrile([18F]FPEB, a radioligand for mGluR5) in hippocampus of adolescent offspring prenatally exposed to LPS, without significant change in the binding of [11C]peripheral benzodiazepine receptor 28 ([11C]PBR28), an inflammatory marker. In addition, dark-light box emergence test revealed a lower level of anxiety in LPS-exposed offspring and this behavioural phenotype was associated with the binding potential of [18F]FPEB in hippocampus. These results confirm that neuroinflammation during developmental phase modulates the physiology of mGluR5 and this alteration can be associated with behavioural phenotype related to anxiety. In addition, this study supports a hypotheses that mGluR5 could be used as a diagnostic target in anxiety.
Cite this paper: Arsenault, D. , Zhu, A. , Gong, C. , Kil, K. , Kura, S. , Choi, J. and Brownell, A. (2014) Hypo-Anxious Phenotype of Adolescent Offspring Prenatally Exposed to LPS Is Associated with Reduced mGluR5 Expression in Hippocampus. Open Journal of Medical Psychology, 3, 202-211. doi: 10.4236/ojmp.2014.33022.

[1]   Niswender, C.M. and Conn, P.J. (2010) Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease. Annual Review of Pharmacology and Toxicology, 50, 295-322.

[2]   Swanson, C.J., Bures, M., Johnson, M.P., et al. (2005) Metabotropic Glutamate Receptors as Novel Targets for Anxiety and Stress Disorders. Nature Reviews Drug Discovery, 4, 131-144.

[3]   Brodkin, J., Busse, C., Sukoff, S.J. and Varney, M.A. (2002) Anxiolytic-Like Activity of the mGluR5 Antagonist MPEP: A Comparison with Diazepam and Buspirone. Pharmacology Biochemistry and Behavior, 73, 359-366.

[4]   Mikulecka, A. and Mares, P. (2009) Effects of mGluR5 and mGluR1 Antagonists on Anxiety-Like Behavior and Learning in Developing Rats. Behavioural Brain Research, 204, 133-139.

[5]   Klodzinska, A., Tatarczynska, E., Chojnacka-Wojcik, E., et al. (2004) Anxiolytic-Like Effects of MTEP, a Potent and Selective mGlu5 Receptor Agonist Does Not Involve GABA(A) Signaling. Neuropharmacology, 47, 342-350.

[6]   Klodzinska, A., Tatarczynska, E., Chojnacka-Wojcik, E. and Pilc, A. (2000) Anxiolytic-Like Effects of Group I Metabotropic Glutamate Antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in Rats. Polish Journal of Pharmacology, 52, 463-466.

[7]   Busse, C.S., Brodkin, J., Tattersall, D., et al. (2004) The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]Pyridine (MTEP) in Rodent Models of Anxiety. Neuropsychopharmacology, 29, 1971-1979.

[8]   Pecknold, J.C., McClure, D.J., Appeltauer, L., Wrzesinski, L. and Allan, T. (1982) Treatment of Anxiety Using Fenobam (a Nonbenzodiazepine) in a Double-Blind Standard (Diazepam) Placebo-Controlled Study. Journal of Clinical Psychopharmacology, 2, 129-133.

[9]   Porter, R.H., Jaeschke, G., Spooren, W., et al. (2005) Fenobam: A Clinically Validated Nonbenzodiazepine Anxiolytic Is a Potent, Selective, and Noncompetitive mGlu5 Receptor Antagonist with Inverse Agonist Activity. Journal of Pharmacology and Experimental Therapeutics, 315, 711-721.

[10]   Hovelso, N., Sotty, F., Montezinho, L.P., et al. (2012) Therapeutic Potential of Metabotropic Glutamate Receptor Modulators. Current Neuropharmacology, 10, 12-48.

[11]   Hermans, E. and Challiss, R.A. (2001) Structural, Signalling and Regulatory Properties of the Group I Metabotropic Glutamate Receptors: Prototypic Family C G-Protein-Coupled Receptors. Biochemical Journal, 359, 465-484.

[12]   Drouin-Ouellet, J., Brownell, A.L., Saint-Pierre, M., et al. (2011) Neuroinflammation Is Associated with Changes in Glial mGluR5 Expression and the Development of Neonatal Excitotoxic Lesions. Glia, 59, 188-199.

[13]   Maelfait, J., Vercammen, E., Janssens, S., et al. (2008) Stimulation of Toll-Like Receptor 3 and 4 Induces Interleukin-1beta Maturation by Caspase-8. The Journal of Experimental Medicine, 205, 1967-1973.

[14]   Ashdown, H., Dumont, Y., Ng, M., et al. (2006) The Role of Cytokines in Mediating Effects of Prenatal Infection on the Fetus: Implications for Schizophrenia. Mol Psychiatry, 11, 47-55.

[15]   Golan, H.M., Lev, V., Hallak, M., Sorokin, Y. and Huleihel, M. (2005) Specific Neurodevelopmental Damage in Mice Offspring Following Maternal Inflammation during Pregnancy. Neuropharmacology, 48, 903-917.

[16]   Guitton, M.J. and Dudai, Y. (2004) Anxiety-Like State Associates with Taste to Produce Conditioned Taste Aversion. Biological Psychiatry, 56, 901-904.

[17]   Latapy, C., Rioux, V., Guitton, M.J. and Beaulieu, J.M. (2012) Selective Deletion of Forebrain Glycogen Synthase Kinase 3beta Reveals a Central Role in Serotonin-Sensitive Anxiety and Social Behaviour. Philosophical Transactions of the Royal Society B: Biological Sciences, 367, 2460-2474.

[18]   Shigemoto, R., Nomura, S., Ohishi, H., et al. (1993) Immunohistochemical Localization of a Metabotropic Glutamate Receptor, mGluR5, in the Rat Brain. Neuroscience Letters, 163, 53-57.

[19]   Venneti, S., Lopresti, B.J. and Wiley, C.A. (2006) The Peripheral Benzodiazepine Receptor (Translocator Protein 18kDa) in Microglia: From Pathology to Imaging. Progress in Neurobiology, 80, 308-322.

[20]   Cai, Z., Pan, Z.L., Pang, Y., Evans, O.B. and Rhodes, P.G. (2000) Cytokine Induction in Fetal Rat Brains and Brain Injury in Neonatal Rats after Maternal Lipopolysaccharide Administration. Pediatric Research, 47, 64-72.

[21]   Panchision, D.M. and McKay, R.D. (2002) The Control of Neural Stem Cells by Morphogenic Signals. Current Opinion in Genetics & Development, 12, 478-487.

[22]   Neugebauer, V. and Carlton, S.M. (2002) Peripheral Metabotropic Glutamate Receptors as Drug Targets for Pain Relief. Expert Opinion on Therapeutic Targets, 6, 349-361.

[23]   Aronica, E., Catania, M.V., Geurts, J., Yankaya, B. and Troost, D. (2001) Immunohistochemical Localization of Group I and II Metabotropic Glutamate Receptors in Control and Amyotrophic Lateral Sclerosis Human Spinal Cord: Upregulation in Reactive Astrocytes. Neuroscience, 105, 509-520.

[24]   Byrnes, K.R., Stoica, B., Riccio, A., Pajoohesh-Ganji, A., Loane, D.J. and Faden, A.I. (2009) Activation of Metabotropic Glutamate Receptor 5 Improves Recovery after Spinal Cord Injury in Rodents. Annals of Neurology, 66, 63-74.

[25]   Aronica, E., van Vliet, E.A., Mayboroda, O.A., Troost, D., Lopes Da Silva, F.H. and Gorter, J.A. (2000) Upregulation of Metabotropic Glutamate Receptor Subtype mGluR3 and mGluR5 in Reactive Astrocytes in a Rat Model of Mesial Temporal Lobe Epilepsy. European Journal of Neuroscience, 12, 2333-2344.

[26]   Geurts, J.J., Wolswijk, G., Bo, L., van der Valk, P., Polman, C.H., Troost, D. and Aronica, E. (2003) Altered Expression Patterns of Group I and II Metabotropic Glutamate Receptors in Multiple Sclerosis. Brain, 126, 1755-1766.

[27]   Byrnes, K.R., Loane, D.J., Stoica, B.A., Zhang, J. and Faden, A.I. (2012) Delayed mGluR5 Activation Limits Neuroin- flammation and Neurodegeneration after Traumatic Brain Injury. Journal of Neuroinflammation, 9, 43.

[28]   Paintlia, M.K., Paintlia, A.S., Barbosa, E., Singh, I. and Singh, A.K. (2004) N-Acetylcysteine Prevents Endotoxin-Induced Degeneration of Oligodendrocyte Progenitors and hypomyelination in Developing Rat Brain. Journal of Neuro-science Research, 78, 347-361.

[29]   Baharnoori, M., Brake, W.G. and Srivastava, L.K. (2009) Prenatal Immune Challenge Induces Developmental Changes in the Morphology of Pyramidal Neurons of the Prefrontal Cortex and Hippocampus in Rats. Schizophrenia Research, 107, 99-109.

[30]   Escobar, M., Crouzin, N., Cavalier, M., Quentin, J., Roussel, J., Lanté, F., Batista-Novais, A.R., Cohen-Solal, C., De Jesus Ferreira, M.C., Guiramand, J., Barbanel, G. and Vignes, M. (2011) Early, Time-Dependent Disturbances of Hippocampal Synaptic Transmission and Plasticity after in Utero Immune Challenge. Biological Psychiatry, 70, 992-999.

[31]   Chlodzinska, N., Gajerska, M., Bartkowska, K., Turlejski, K. and Djavadian, R.L. (2011) Lipopolysaccharide Injected to Pregnant Mice Affects Behavior of Their Offspring in Adulthood. Acta Neurobiologiae Experimentalis, 71, 519-527.

[32]   Yin, P., Liu, J., Li, Z., Wang, Y.Y., Qiao, N.N., Huang, S.Y., Li, B.M. and Sun, R.P. (2013) Prenatal Immune Challenge in Rats Increases Susceptibility to Seizure-Induced Brain Injury in Adulthood. Brain Research, 1519, 78-86.

[33]   Gray, J.A. and McNaughton, N. (2000) The Neuropsychology of Anxiety. 2nd Edition, Oxford University Press, Oxford.

[34]   Deacon, R.M., Bannerman, D.M. and Rawlins, J.N. (2002) Anxiolytic Effects of Cytotoxic Hippocampal Lesions in Rats. Behavioral Neuroscience, 116, 494-497.

[35]   McHugh, S.B., Deacon, R.M., Rawlins, J.N. and Bannerman, D.M. (2004) Amygdala and Ventral Hippocampus Contribute Differentially to Mechanisms of Fear and Anxiety. Behavioral Neuroscience, 118, 63-78.

[36]   Engin, E. and Treit, D. (2007) The Role of Hippocampus in Anxiety: Intracerebral Infusion Studies. Behavioural Pharmacology, 18, 365-374.