Altered GABA transmission in a mouse model of increased trait anxiety

Abstract

Anxiety disorders are the most prevalent central nervous system diseases imposing a high social burden to our society. Emotional processing is particularly controlled by GABA-ergic transmission in the amygdala. Using in situ hybridization and immunohistochemistry we now investigated changes in the expression of GABA synthesizing enzymes (GAD65 and GAD67), GABAA (α1–5, β1–3, γ1–2) and GABAB receptor subunits (GBBR1, GBBR2) in amygdaloid nuclei of high anxiety-related behavior (HAB) mice in comparison to mice selected for normal anxiety-related behavior (NAB). Levels of GAD65 and GAD67 mRNAs and protein, as well as those of GABA were increased in the amygdala of HAB mice. Relative to NAB controls, mRNA expression of the GABAA receptor subunits β1, β2 and γ2 was specifically increased in the basolateral amygdala of HAB mice while transcription of α5 and γ1 subunits was reduced in the central and medial amygdala. On the protein level, increases in β2 and γ2 subunit immunoreactivities were evident in the basolateral amygdala of HAB mice. No change in GABAB receptor expression was observed. These findings point towards an imbalanced GABA-ergic neurotransmission in the amygdala of HAB mice. On the other hand, FosB, a marker for neuronal activity, was increased in principal neurons of the basolateral amygdala in HAB mice, reflecting activation of excitatory neurons, possibly as a consequence of reduced GABA-ergic tonic inhibition through α5 and γ1 containing receptors. Ultimately these mechanisms may lead to the compensatory activation of GABA transmission, as indicated by the increased expression of GAD65/67 in HAB mice.

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

“…Moreover, the increased TH and GAD 67 expression reported herein might or might not be associated with elevated DA or GABA neurotransmission. However, rat and mouse studies indicate simultaneous elevations in TH or GAD 67 mRNA expression and dialysate (extracellular) DA or GABA levels in the VTA or the amygdala, respectively, suggesting concurrent increases in DA or GABA neurotransmission and related mRNA expression (Ding et al, 1998;Ferrari et al, 2002;Tasan et al, 2011).…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…In contrast, increased GABA transmission was shown in a mouse model of increased trait anxiety [105]. Tph2 2/2 mice exhibited an altered anxietyrelated phenotype with a dissociation of innate anxiety-like behaviour and conditioned fear responses but unchanged GABA concentrations.…”

Differential Effect of Unilateral Amygdalar GABA<sub>A</sub> Receptor Agonist Injection on Low- and High-Anxiety Rats

“…The level of GABA receptors containing α5 and γ1 subsunits is lower in the central and medial amygdala of high anxietyrelated behavior (HAB) mice than in mice with normal anxiety-like behavior (NAB). Furthemore, marker for neuronal activity (FosB) is increased in principal neuron of the basolateral amygdala of HAB mice, reflecting activation of excitatory neurons [7]. Rats with low freezing response in the contextual fear test have higher GABA concentration in the basolateral amygdala if compares to the rats with high freezing response in the contextual fear test [6].…”