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The Neurodevelopmental Profile of Group 1 Metabotropic Glutamate Receptors: Implications for Novel Therapeutics

Journal Article


Abstract


  • Background: Group I metabotropic glutamate receptor (mGluR1 and mGluR5) allosteric modulators are currently being investigated as novel therapeutics for the treatment of neurodevelopmental disorders such as schizophrenia, autism, depression (Cleva and Olive, 2011). Recent evidence suggests that allosteric modulators have adverse pharmacological effects when bound to the monomeric, compared to the dimeric form of these receptors (El Moustaine et al., 2012). Investigating the neurodevelopmental expression of dimeric and monomeric mGluR1 and mGluR5 may highlight possible implications for novel therapeutics at critical neurodevelopmental periods.

    Methods: Pregnant Sprague-Dawley rats were obtained at gestational day 14. Offspring were euthanised on postnatal day (PN) 12, 35 and 96 (n=6/group) coinciding with juvenile, adolescent and adult time points. Immunoblots were performed on prefrontal cortex (PFC) and hippocampal tissue under non-reducing conditions to measure dimeric and monomeric mGluR1 and mGluR5 proteins.

    Results: Dimeric mGluR1and mGluR5 was expressed in higher abundance than their monomeric forms. mGluR1 dimeric expression was lowest at PN12 in both the PFC and hippocampus; where it displayed an increase with age. Whilst monomeric mGluR1 expression was considerably lower, it showed a similar trend in the PFC, however, its expression remained constant in the hippocampus. In contrast, dimeric mGluR5 protein expression in the PFC peaked at PN12 and decreased throughout the neurodevelopmental time-points, however its expression in the hippocampus remained constant throughout. Interestingly, in both regions mGluR5 monomer was highly expressed at PN12, almost equal to dimeric expression and then declined to the lowest limits of detection at later time-points.

    Conclusion: The monomeric form of mGluR5 is relatively abundant during early post-natal development. Considering positive allosteric modulators exert an unregulated agonist effect when bound to the monomeric form of mGluRs, administration of these compounds during such a critical neurodevelopmental period, may cause seizures and neurotoxic effects, posing possible consequences for novel mGluR5 therapeutics.

Publication Date


  • 2016

Citation


  • Lum, J. S., Ooi, L., Matosin, N., Andrews, J., Huang, X., Fernandez, F. & Newell, K. A. (2016). The Neurodevelopmental Profile of Group 1 Metabotropic Glutamate Receptors: Implications for Novel Therapeutics. International Journal of Neuropsychopharmacology, 19 (Suppl. 1), 78-79.

Number Of Pages


  • 1

Start Page


  • 78

End Page


  • 79

Volume


  • 19

Issue


  • Suppl. 1

Place Of Publication


  • United Kingdom

Abstract


  • Background: Group I metabotropic glutamate receptor (mGluR1 and mGluR5) allosteric modulators are currently being investigated as novel therapeutics for the treatment of neurodevelopmental disorders such as schizophrenia, autism, depression (Cleva and Olive, 2011). Recent evidence suggests that allosteric modulators have adverse pharmacological effects when bound to the monomeric, compared to the dimeric form of these receptors (El Moustaine et al., 2012). Investigating the neurodevelopmental expression of dimeric and monomeric mGluR1 and mGluR5 may highlight possible implications for novel therapeutics at critical neurodevelopmental periods.

    Methods: Pregnant Sprague-Dawley rats were obtained at gestational day 14. Offspring were euthanised on postnatal day (PN) 12, 35 and 96 (n=6/group) coinciding with juvenile, adolescent and adult time points. Immunoblots were performed on prefrontal cortex (PFC) and hippocampal tissue under non-reducing conditions to measure dimeric and monomeric mGluR1 and mGluR5 proteins.

    Results: Dimeric mGluR1and mGluR5 was expressed in higher abundance than their monomeric forms. mGluR1 dimeric expression was lowest at PN12 in both the PFC and hippocampus; where it displayed an increase with age. Whilst monomeric mGluR1 expression was considerably lower, it showed a similar trend in the PFC, however, its expression remained constant in the hippocampus. In contrast, dimeric mGluR5 protein expression in the PFC peaked at PN12 and decreased throughout the neurodevelopmental time-points, however its expression in the hippocampus remained constant throughout. Interestingly, in both regions mGluR5 monomer was highly expressed at PN12, almost equal to dimeric expression and then declined to the lowest limits of detection at later time-points.

    Conclusion: The monomeric form of mGluR5 is relatively abundant during early post-natal development. Considering positive allosteric modulators exert an unregulated agonist effect when bound to the monomeric form of mGluRs, administration of these compounds during such a critical neurodevelopmental period, may cause seizures and neurotoxic effects, posing possible consequences for novel mGluR5 therapeutics.

Publication Date


  • 2016

Citation


  • Lum, J. S., Ooi, L., Matosin, N., Andrews, J., Huang, X., Fernandez, F. & Newell, K. A. (2016). The Neurodevelopmental Profile of Group 1 Metabotropic Glutamate Receptors: Implications for Novel Therapeutics. International Journal of Neuropsychopharmacology, 19 (Suppl. 1), 78-79.

Number Of Pages


  • 1

Start Page


  • 78

End Page


  • 79

Volume


  • 19

Issue


  • Suppl. 1

Place Of Publication


  • United Kingdom