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

Abstract

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: wildtype, GCPII hypomorphs, and wildtypes 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, pre-pulse inhibition, and spatial memory. Wildtype 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 wildtype 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.

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

“…In contrast, the social interaction deficit observed in mice deficient for the GPCII, which catalyse the absorption of folates, was not affected by sex (Schaevitz et al, 2012). Finally, no sex difference was observed in COMT-/-mice that showed similar social recognition to the control groups (Babovic et al, 2008) (Table 2).…”

“…When investigating signalling pathways potentially involved in schizophrenia such as folate depletion (Schaevitz et al, 2012), a sex difference in social interaction was also observed.…”

“…This is usually the case for several domains of cognition where the tests show intact learning (Barnes maze, Radial maze, Morris Water maze) or performance (Y maze, novel object recognition). A comparison of the experimental group versus the sex-matched control group is mostly used to indirectly highlight a sex difference in rodent models for schizophrenia (Andersen and Pouzet, 2004;Ayhan et al, 2011;Bitanihirwe et al, 2010;Engmann et al, 2011;Hill et al, 2014;Karl et al, 2010;LlorenteBerzal et al, 2012;Markham et al, 2010;Pletnikov et al, 2008;Ryan et al, 2011;Schaevitz et al, 2012;Sircar, 2003;Snigdha et al, 2011;von Wilmsdorff et al, 2010;Wischhof et al, 2015). In all studies we consider, unless otherwise specified, the appropriate control group was used for comparison of the deficit induced by the model in both sexes.…”

“…It is important to mention that no sex difference was found in two studies investigating MWM performance in some strains of genetically modified mice with candidate genes that contribute a susceptibility to schizophrenia such as the v-akt murine thymoma viral oncogene homolog 1 (Akt1) (Chen and Lai, 2011), or signalling pathways that are involved in schizophrenia such as the glutamate carboxypeptidase II (GCPII) and folate depletion (Schaevitz et al, 2012) that interact within the one-carbon metabolic pathway and/or modulate the glutamatergic system ( Table 2).…”

Gene-Environment Interactions and Epigenetic Pathways in Autism: The Importance of One-Carbon Metabolism

“…Betaine-induced improvements were attributed to an increase in the remethylation of homocysteine to methionine through an alternate reaction using betaine and BHMT instead of 5-MTHF and MTR. Surprisingly, folate depletion rescued social interaction impairments in GCPII +/-mice (Schaevitz et al 2012). We hypothesize that the normalization of brain folate levels (through reduced folate intake) restores methylation potential and rescues the behavior impairment in the GCPII +/-mice.…”