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Neurochem Res. 2018 Aug;43(8):1683-1691. doi: 10.1007/s11064-018-2584-x. Epub 2018 Jun 23.

Chronic Adolescent CDPPB Treatment Alters Short-Term, but not Long-Term, Glutamatergic Receptor Expression.

Lum JS1,2,3, Millard SJ4,5, Frank E5,6, Matosin N4,5,6, Huang XF4,5, Ooi L5,7, Newell KA4,5.

Author information

1
School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia. jsl934@uowmail.edu.au.
2
Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia. jsl934@uowmail.edu.au.
3
Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, NSW, 2010, Australia. jsl934@uowmail.edu.au.
4
School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia.
5
Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.
6
Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, NSW, 2010, Australia.
7
School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia.

Abstract

Dysfunction of the glutamatergic system is believed to underlie many neurodevelopmental disorders including autism, Rett syndrome and schizophrenia. Metabotropic glutamate receptor (mGluR5) positive allosteric modulators (PAM) potentiate glutamatergic signaling, particularly indirectly via the NMDA receptor. Preclinical studies report mGluR5 PAMs can improve schizophrenia-relevant behaviours. Furthermore, adolescent administration has shown to prevent cognitive induced deficits in adult rodents. However, there is limited understanding of the short- and long-term neurochemical effects of mGluR5 PAMs, which may underlie their therapeutic effects. We examined the effect of 7-day adolescent (PN28-34) treatment with the mGluR5 PAM, CDDPB (30 mg/kg), on glutamatergic receptor expression at adolescence (PN35) and adulthood (PN96). Immunoblot analysis revealed that 7-day adolescent CDPPB treatment increased protein expression of glutamatergic receptors including the NMDA receptor subunits, NR1 and NR2A and the AMPA subunits (GluA1 and GluA2) in the adolescent hippocampus, changes that did not extend to adulthood. In contrast, there were no changes in the adolescent frontal cortex, however elevated mGluR5 protein expression was observed at adulthood following adolescent CDPPB treatment. The present study indicates adolescent CDPPB treatment may cause brain region dependent effects on the glutamatergic system, which do not persist into adulthood. These findings may have implications for the preclinical development of mGluR5 PAMs for the treatment of neurodevelopmental disorders.

KEYWORDS:

Adolescence; CDPPB; Frontal cortex; Hippocampus; Metabotropic glutamate 5 receptor positive allosteric modulator; NMDA

PMID:
29936568
DOI:
10.1007/s11064-018-2584-x
[Indexed for MEDLINE]

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