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

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.

Perinatal exposure to fluoxetine increases anxiety- and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression

“…In light of these findings, it is tempting to speculate that the paralleled reductions of PSD-95 and NMDA receptor subunits in the PFC, could be indicative of overall reductions in post-synaptic densities, the specialised sites of glutamatergic synapses that harbour key proteins responsible for glutamatergic signalling and transduction (Sheng, 2001). However, in the vHPC, whilst we also report reduced PSD-95 in FLX-exposed offspring, we observed no change in NMDA receptor subunits and increased levels of mGluR5 dimers and the associated scaffolding protein, Homer1b/c (which positively regulates mGluR5 signalling (Lum et al, 2018)), two proteins also indirectly coupled to PSD-95 via complexes deep in the post-synaptic density (Sheng and Kim, 2011) suggesting that SSRI exposure induces brain region-specific effects.…”

Lrrc7 mutant mice model developmental emotional dysregulation that can be alleviated by mGluR5 allosteric modulation

“…33 ). For repeated treatment, there are also indirect effects of mGluR5 PAMs on the expression of NMDA receptors in specific brain regions in rat models 55 .…”