Bernhard Lüscher | Eberly College of Science

We are working to improve our understanding of the role and function of GABAergic transmission in health and disease. GABA (gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain and known to exert most of its function by activation of so-called GABA(A) receptors. These receptors are GABA-gated chloride channels, and they serve as the targets of multiple classes of clinically and therapeutically important psychoactive drugs, most notably benzodiazepines (i.e., Valium, Xanax, Versed, etc.). Based on knowledge derived from these drugs, GABA(A) receptors are known to modulate virtually every higher-order brain function (learning, memory, cognition, emotion, pain, motivation, muscle tension, etc).

A first line of research uses mouse genetics to model and investigate the molecular mechanisms underlying neuropsychiatric disorders. In particular, we are interested in the etiology of Major Depressive Disorder (MDD), a leading cause of total disability affecting about 17 percent of the human population at least once in their lives. Recent clinical evidence points to functional impairment of certain GABA-releasing interneurons and reduced brain concentrations of GABA as a likely cause of MDD. Using targeted mutagenesis in mice, we have shown that modest deficits in GABAergic neuronal inhibition are sufficient to reproduce behavioral, cognitive, cellular, endocrine, and pharmacological alterations expected of a mouse model of depression. These mice, therefore, provide strong evidence that the reduced GABA concentrations found in patients are not just an epiphenomenon of MDD, and that they can be causal for MDD (reviewed in Luscher et al. 2011, Mol. Psychiatry; Luscher and Mohler, 2019, F1000Research). Further analyses of these mice revealed that defects in GABAergic transmission can be causal for defects in the function of glutamate implicated in MDD and that the deficiencies in both GABA and glutamate function can be reversed for prolonged periods with the rapid-acting antidepressant, ketamine (Ren et al. 2016)

In a second line of research, we are elucidating the mechanisms of antidepressant drug action. It is becoming increasingly clear that antidepressants act to ultimately increase and normalize GABAergic synaptic transmission even if they are designed to enhance the function of other neurotransmitters (serotonin, norepinephrine, glutamate, and their receptors). Therefore, we asked whether genetically enhancing the function of certain GABA-releasing interneurons would be sufficient to mimic the molecular and behavioral effects of antidepressant drug treatments. We showed that genetically increasing the excitability of GABA-producing interneurons known as somatostatin cells reproduced both biochemical and behavioral consequences of antidepressant drug treatment (Fuchs et al. 2017). Similar to antidepressant drug treatments, these same neural circuit manipulations also resulted in behavioral resilience to the detrimental effects of chronic stress exposure (Jefferson et al. 2020, Shao et al. 2024), and they allowed the reversal of the detrimental effects of prior stress exposure (Jiang et al. 2024). Surprisingly, the brain regions that mediate antidepressant-like effects of GABAergic inhibition were found to be strictly stress-specific. Moreover, prolonged increases in GABAergic inhibition of pyramidal cells resulted in paradoxically increased rather than reduced activity of these cells (Jiang et al. 2024). Transcriptome changes that underlie GABAergic mechanisms of stress resilience hold the promise of informing novel therapeutic strategies for stress-associated psychiatric disorders (Shao et al. 2024). The focus of our ongoing research is on the microcircuits and molecular mechanisms underlying the vulnerability and resilience to chronic stress exposure, including sex differences of the relevant neural substrates (Shao et al. 2024, Jiang et al 2024). (For References, see the link to Google Scholar)

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