Differential levels of glutamate dehydrogenase 1 (GLUD1) in Balb/c and C57BL/6 mice and the effects of overexpression of the Glud1 gene on glutamate release in striatum

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with C57BL/6. Using an enzyme-based MEA (microelectrode array) that is selective for measuring glutamate in vivo, we measured depolarization-induced glutamate release. Within a discrete layer of the striatum, glutamate release was significantly increased in Balb/c Tg mice compared with wt (wild-type) littermates. Furthermore, Balb/c mice released approx. 50–60% of the amount of glutamate compared with C57BL/6 mice. This is similar to the lower levels of endogenous GLUD1 protein in Balb/c compared with C57BL/6 mice. The development of these Glud1-overexpressing mice may allow for the exploration of key molecular events produced by chronic exposure of neurons to moderate, transient increases in glutamate release, a process hypothesized to occur in neurodegenerative disorders.This work was supported by the NSF (National Science Foundation) [grant number EEC-0310723]; NIH/NIDA (National Institutes of Health/National Institute on Drug Abuse) [grant number DA017186]; CEBRA, Phase II, NIA, [grant number AG12993]; NIAAA (National Institute of Alcohol Abuse and Alcoholism) [grant numbers AA11419, AA04732, AA12276]; NSF [grant numbers DBI-9987807, DBI-0352848]; NIDA [grant number DA017186]; NINDS (National Institute of Neurological Disorders and Strokes) [grant number NS39787]; NIMH (National Institute of Mental Health) [grant number MH58414]; NIDA Training [grant number DA022738]; NIDA [grant number DA015088], The Kansas Technology Enterprise Corporation, The Miller, Hedwig and Wilbur Fund, and The University of Kansas Research Development Fund