Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: Implications for neurodevelopmental disorders

• Published in: Developmental neurobiology (Hoboken, N.J.) N.J.), 2012-06, Vol.72 (6), p.891-905
• Main Authors: Schaevitz, Laura R., Picker, Jonathan D., Rana, Jasmine, Kolodny, Nancy H., Shane, Barry, Berger‐Sweeney, Joanne E., Coyle, Joseph T.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - physiology; Cognition Disorders - genetics; Cognition Disorders - physiopathology; Female; folate; Folic Acid Deficiency - physiopathology; Gene-Environment Interaction; gene‐environment interactions; glutamate; glutamate carboxypeptidase II; Glutamate Carboxypeptidase II - genetics; Haploinsufficiency; Male; Maze Learning - physiology; Mice; Mice, Transgenic; Motor Activity - physiology; one‐carbon metabolism; Rotarod Performance Test; Social Behavior
• ISSN: 1932-8451; 1932-846X
• DOI: 10.1002/dneu.21000

Interactions between genetic and environmental risk factors underlie a number of neuropsychiatric disorders, including schizophrenia (SZ) and autism (AD). Due to the complexity and multitude of the genetic and environmental factors attributed to these disorders, recent research strategies focus on elucidating the common molecular pathways through which these multiple risk factors may function. In this study, we examine the combined effects of a haplo‐insufficiency of glutamate carboxypeptidase II (GCPII) and dietary folic acid deficiency. In addition to serving as a neuropeptidase, GCPII catalyzes the absorption of folate. GCPII and folate depletion interact within the one‐carbon metabolic pathway and/or of modulate the glutamatergic system. Four groups of mice were tested: wild‐type, GCPII hypomorphs, and wild‐types and GCPII hypomorphs both fed a folate deficient diet. Due to sex differences in the prevalence of SZ and AD, both male and female mice were assessed on a number of behavioral tasks including locomotor activity, rotorod, social interaction, prepulse inhibition, and spatial memory. Wild‐type mice of both sexes fed a folic acid deficient diet showed motor coordination impairments and cognitive deficits, while social interactions were decreased only in males. GCPII mutant mice of both sexes also exhibited reduced social propensities. In contrast, all folate‐depleted GCPII hypomorphs performed similarly to untreated wild‐type mice, suggesting that reduced GCPII expression and folate deficiency are mutually protective. Analyses of folate and neurometabolite levels associated with glutamatergic function suggest several potential mechanisms through which GCPII and folate may be interacting to create this protective effect. © 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 891–905, 2012