Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith

One of the leading hypotheses of the etiology of schizophrenia is glutamatergic hypofunction (22) (23) (24) . N-methyl-D-aspartate subtype glutamate (NMDA) receptor dysfunction is strongly implicated in the pathophysiology of schizophrenia, particularly in human pharmacological studies (25) (26) (27) (28) . Converging evidence suggests that NMDA receptor hypofunction may actually reflect a dysregulation at the receptor level, including mutations in NMDA receptor subunits (29) . Several studies have found associations between the gene that encodes the GluN1 subunit of the NMDA receptor (Grin1) and schizophrenia (30) (31) (32) (33) (34) (35) (36) (37) (38) . The GluN1 knockdown mouse model has a ~90% global reduction of normal functioning NMDA receptors, achieved by targeted insertion of 2 kb of foreign DNA into intron 19 of the Grin1 gene (39) . Additionally, mice with mutations in the Grin1 gene have well-characterized behavioral endophenotypes for schizophrenia; this includes impairments in executive function and working memory, increased stereotypic behavior, decreased anxiety-like behavior, decreased sensorimotor gating, and abnormal social interaction (40) . Several of these behaviors are attenuated with typical and atypical antipsychotics at doses similar to those used in pharmacological models of schizophrenia (MK-801 or phencyclidine models), including hyperactivity, stereotypy, and sociability deficits (39, 41) . Therefore, the GluN1 knockdown mouse model is a viable and useful tool for studying the interface of NMDA receptor hypofunction, bioenergetics, and schizophrenia symptomology.