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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
Journal article   Open access   Peer reviewed

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

Meng-Lin Li, Yelena Gulchina, Sarah A. Monaco, Bo Xing, Brielle R. Ferguson, Yan-Chun Li, Feng Li, Xi-Quan Hu and Wen-Jun Gao
Neurobiology of learning and memory, v 140, pp 52-61
Apr 2017
DOI: https://doi.org/10.1016/j.nlm.2017.02.004
PMID: 28213064
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc5860881View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Animal model Cognitive function MGluR2/3 NMDA receptor Prefrontal cortex Schizophrenia
•Gestational MAM exposure induced a significant decrease in NMDAR expression.•LY39 treatment effectively recovers the disrupted NMDAR expression in MAM rats.•Early treatment targeting mGluR2 alleviates learning and cognitive flexibility deficits.•Targeting NMDARs during early stages of SCZ could be an effective strategy. 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.

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18 citations in Scopus

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Behavioral Sciences
Neurosciences
Psychology
Psychology, Multidisciplinary
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