Genetic deletion of the 67‐kDa isoform of glutamate decarboxylase alters conditioned fear behavior in rats

Abstract

The GABAergic system is thought to play an important role in the control of cognition and emotion, such as fear, and is related to the pathophysiology of psychiatric disorders. For example, the expression of the 67-kDa isoform of glutamate decarboxylase (GAD67), a GABA-producing enzyme, is downregulated in the postmortem brains of patients with major depressive disorder and schizophrenia. However, knocking out the Gad1 gene, which encodes GAD67, is lethal in mice, and thus, the association between Gad1 and cognitive/emotional functions is unclear. We recently developed Gad1 knockout rats and found that some of them can grow into adulthood. Here, we performed fear-conditioning tests in adult Gad1 knockout rats to assess the impact of the loss of Gad1 on fear-related behaviors and the formation of fear memory. In a protocol assessing both cued and contextual memory, Gad1 knockout rats showed a partial antiphase pattern of freezing during training and significantly excessive freezing during the contextual test compared with wild-type rats. However, Gad1 knockout rats did not show any synchronous increase in freezing with auditory tones in the cued test. On the other hand, in a contextual memory specialized protocol, Gad1 knockout rats exhibited comparable freezing behavior to wildtype rats, while their fear extinction was markedly impaired. These results suggest that GABA synthesis by GAD67 has differential roles in cued and contextual fear memory.

Behavioral Consequences of a Combination of Gad1 Haplodeficiency and Adolescent Exposure to an NMDA Receptor Antagonist in Long-Evans Rats

“…Third, we also observed a slight delay in fear extinction in the HET group. This result is similar to the findings of previous studies in amygdalaspecific Gad1 knockdown mice (Heldt et al, 2012), PV neuronspecific Gad1 knockdown mice (Brown et al, 2015), and Gad1 −/− rats (Fujihara et al, 2020b). Considering that amygdala-specific knockdown is sufficient to cause this phenotype, the reduction of GAD67 and subsequent impairment in GABAergic transmission in the amygdala may be responsible for this behavior in HET rats as well.…”

“…Seven days after the last injection of MK-801, we started the behavioral test battery. The acoustic startle response (including a prepulse inhibition [PPI]), Y-maze, elevated plus-maze, open field, social interaction, forced swim, and fear conditioning tests were conducted as described previously with minor modifications (Fujihara et al, 2015a;Miyata et al, 2019;Fujihara et al, 2020a, Fujihara et al, 2020b. The test battery was performed in the above-mentioned order (see Supplementary Table S1).…”

Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits

“…However, a selective ablation of GAD67 in somatostatin interneurons has been shown to enhance anxiety like behavior ( Miyata et al, 2019 ). Moreover, a recent study in GAD67 knock out rats has also demonstrated enhancement of contextual fear memory ( Fujihara et al, 2021 ). We propose these gene-dosage -dependent and isozyme-specific effects to be related to a differential role of GAD65 and GAD67 in the dDG and vDG during stressful experiences.…”

The Anxiolytic effect of salicylic acid is mediated via the GABAergic system

“…These authors showed that chronic stress induced (GAD65) mRNA expression whereas acute stress selectively increased (GAD67) mRNA in the hypothalamus and hippocampus. In a recent study, it was also shown that the loss of (Gad67) function, altered conditioned fear behavior in adult rats (Fujihara et al 2020). As we were assessing an acute anxiety model, we evaluated the effect of salicylic acid on (GAD 67) but not (GAD65) expression.…”