Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice

Abstract

Reduced expression of glutamate decarboxylase 67 (GAD67), encoded by the Gad1 gene, is a consistent finding in postmortem brains of patients with several psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. The dysfunction of GAD67 in the brain is implicated in the pathophysiology of these psychiatric disorders; however, the neurobiological consequences of GAD67 dysfunction in mature brains are not fully understood because the homozygous Gad1 knockout is lethal in newborn mice. We hypothesized that the tetracycline-controlled gene expression/suppression system could be applied to develop global GAD67 knockdown mice that would survive into adulthood. In addition, GAD67 knockdown mice would provide new insights into the neurobiological impact of GAD67 dysfunction. Here, we developed Gad1tTA/STOP−tetO biallelic knock-in mice using Gad1STOP−tetO and Gad1tTA knock-in mice, and compared them with Gad1+/+ mice. The expression level of GAD67 protein in brains of Gad1tTA/STOP−tetO mice treated with doxycycline (Dox) was decreased by approximately 90%. The GABA content was also decreased in the brains of Dox-treated Gad1tTA/STOP−tetO mice. In the open-field test, Dox-treated Gad1tTA/STOP−tetO mice exhibited hyper-locomotor activity and decreased duration spent in the center region. In addition, acoustic startle responses were impaired in Dox-treated Gad1tTA/STOP−tetO mice. These results suggest that global reduction in GAD67 elicits emotional abnormalities in mice. These GAD67 knockdown mice will be useful for elucidating the neurobiological mechanisms of emotional abnormalities, such as anxiety symptoms associated with psychiatric disorders.

Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish—implications for neurodevelopmental disorders

“…Similarly, animal models support the notion of GABA playing a yet underrated role in the pathophysiology of NDDs. Genetic mouse models with impaired function GABAergic signalling components mirror core ADHD symptoms such as hyperactivity, impaired sustained attention and increased impulsivity [42][43][44][45]. Interestingly, hyperactivity in the Gat1 knockout mice was rescued by stimulant application [45].…”

“…control and show that foxp2 loss-of-function results in increased locomotor activity. Interestingly, impaired Gad1 function is implicated in altered motor function [43,66]. Hence, we hypothesised that Gad1-activity is important for the regulation of locomotor behaviour in zebrafish larvae.…”

“…The relevance of compromised GABA-mediated inhibition for the aetiology of NDDs is supported by multiple findings both in humans and in model organisms. In human, variants of genes encoding for GABAergic signalling components are associated with ADHD [38][39][40][41], and mice with genetic disruption of GABAergic signalling components mirror core ADHD symptoms [42][43][44][45]. Further, structural brain imaging in ADHD patients shows alterations in regions with prominent GABAergic neuron populations, such as the striatum [46].…”

Genetic polymorphism and neuroanatomical changes in schizophrenia

“…Recent studies in mice have demonstrated that reducing the expression of GAD67, up to its definitive blocking, causes emotional abnormalities and alters conditioned fear behavior. Thus, the fear of certain objects or certain contexts, which in the past represented a danger, disappears [ 44 ]. GABA synthesis, produced by GAD67, has an important role in the contextualization and differentiation of fear memory.…”

Site‐directed mutagenesis improves the practical application of L‐glutamic acid decarboxylase inEscherichia coli

“…GABA plays an important role in improving the physiological function of the body and is often used as a drug and food addition. In the pharmaceutical industry, GABA has an anticonvulsant function [ 1 ] and is used to treat epilepsy [ 2 ], anxiety [ 3 ], and in adjuvant treatment of Parkinson's disease [ 4 ]. As a food addition, GABA is often added to beverages, alcohol, and milk to prevent neurological diseases [ 5 ].…”