ly-379268 and Learning-Disabilities

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-3β (GSK3β). 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.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Spines; Disease Models, Animal; Excitatory Amino Acid Agonists; Female; Glycogen Synthase Kinase 3 beta; Learning Disabilities; Methylazoxymethanol Acetate; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Schizophrenia; Tissue Culture Techniques