Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes in adult by acting through GSK3ß.
Neuropharmacology
; 137: 359-371, 2018 07 15.
Article
en En
| MEDLINE
| ID: mdl-29793154
Prodromal memory deficits represent an important marker for the development of schizophrenia (SZ), in which glutamatergic hypofunction occurs in the prefrontal cortex (PFC). The mGluR2/3 agonist LY379268 (LY37) attenuates excitatory N-methyl-D-aspartate receptor (NMDAR)-induced neurotoxicity, a central pathological characteristic of glutamatergic hypofunction. We therefore hypothesized that early treatment with LY37 would rescue cognitive deficits and confer benefits for SZ-like behaviors in adults. To test this, we assessed whether early intervention with LY37 would improve learning outcomes in the Morris Water Maze for rats prenatally exposed to methylazoxymethanol acetate (MAM), a neurodevelopmental SZ model. We found that a medium dose of LY37 prevents learning deficits in MAM rats. These effects were mediated through postsynaptic mGluR2/3 via improving GluN2B-NMDAR function by inhibiting glycogen synthase kinase-3ß (GSK3ß). Furthermore, dendritic spine loss and learning and memory deficits observed in adult MAM rats were restored by juvenile LY37 treatment, which did not change prefrontal neuronal excitability and glutamatergic synaptic transmission in adult normal rats. Our results provide a mechanism for mGluR2/3 agonists against NMDAR hypofunction, which may prove to be beneficial in the prophylactic treatment of SZ.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Esquizofrenia
/
Antipsicóticos
/
Agonistas de Aminoácidos Excitadores
/
Compuestos Bicíclicos Heterocíclicos con Puentes
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Glucógeno Sintasa Quinasa 3 beta
/
Aminoácidos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Pregnancy
Idioma:
En
Revista:
Neuropharmacology
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido