Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia

Abstract

Schizophrenia (SCZ) is a neurodevelopmental psychiatric disorder, in which cognitive function becomes disrupted at early stages of the disease. Although the mechanisms underlying cognitive impairments remain unclear, N-methyl-D-aspartate receptors (NMDAR) hypofunctioning in the prefrontal cortex (PFC) has been implicated. Moreover, cognitive symptoms in SCZ are usually unresponsive to treatment with current antipsychotics and by onset, disruption of the dopamine system, not NMDAR hypofunctioning, dominates the symptoms. Therefore, treating cognitive deficits at an early stage is a realistic approach. In this study, we tested whether an early treatment targeting mGluR2 would be effective in ameliorating cognitive impairments in the methylazoxymethanol acetate (MAM) model of SCZ. We investigated the effects of an mGluR2 agonist/mGluR3 antagonist, LY395756 (LY39), on the NMDAR expression and function in juveniles, as well as cognitive deficits in adult rats after juvenile treatment. We found that gestational MAM exposure induced a significant decrease in total protein levels of the NMDAR subunit, NR2B, and a significant increase of pNR2BTyr1472 in the juvenile rat PFC. Treatment with LY39 in juvenile MAM-exposed rats effectively recovered the disrupted NMDAR expression. Furthermore, a subchronic LY39 treatment in juvenile MAM-exposed rats also alleviated the learning deficits and cognitive flexibility impairments when tested with a cross-maze based set-shifting task in adults. Therefore, our study demonstrates that targeting dysfunctional NMDARs with an mGluR2 agonist during the early stage of SCZ could be an effective strategy in preventing the development and progression in addition to ameliorating cognitive impairments of SCZ.

Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia

“…; Li et al . ). NR2B protein levels are substantially reduced, as shown by western blot analysis, but this approach cannot distinguish the regional or laminar specificity of this deficiency.…”

“…; Li et al . ). Pups were usually born on E21/P0, and were weaned and rehoused on postnatal day 21 (P21).…”

Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes in adult by acting through GSK3β

“…In our recent study (Li et al, 2017), we found that targeting mGluR2/3 in the early stage can correct NMDAR hypofunction and has a beneficial effect for cognition deficits observed in adult MAM rats. However, the mechanism of how it works was untested.…”

“…Specifically, activation of mGluR2/3 negatively modulates synaptic transmission by reducing presynaptic glutamate release (Mateo and Porter, 2007). In contrast, postsynaptic mGluR2/3 enhances neuronal excitability (Jin et al, 2017) and AMPARs and NMDARs function directly (Li et al, 2017; Li et al, 2015a; Li et al, 2015b; Tyszkiewicz et al, 2004; Wang et al, 2013; Xi et al, 2011). Although clinical trials of mGluR2/3 agonists in adult patients with SZ have yielded controversial results (Downing et al, 2014; Patil et al, 2007), emerging data suggest that pharmacological activation of mGluR2/3 modulates glutamate neurotransmission and affects NMDAR function, holding the promise of this treatment strategy for the glutamate hypofunction hypothesis (Li et al, 2015a).…”

The role of microbiota in the pathogenesis of schizophrenia and major depressive disorder and the possibility of targeting microbiota as a treatment option

“…In a recent study Li et al first described a decrease in NMDA receptor expression in an animal model, and then by treating the animals with LY39, an agonist of mGluR, corrected the disrupted NMDA receptor expression. Furthermore, they observed that learning deficits and cognitive flexibility improved in treated animals, and thus found a correlation between the expression level of BDNF and NMDA and the symptoms of schizophrenia [ 26 ]. In a germ free mice line, decreased expression levels of BDNF and NMDA receptors were found in the cortex and hippocampus [ 27 ].…”