GABAergic Control of Depression-Related Brain States

Lüscher, Bernhard; Fuchs, Thomas

doi:10.1016/bs.apha.2014.11.003

Cited by 125 publications

(77 citation statements)

References 323 publications

(399 reference statements)

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“…For instance, human and animal studies have demonstrated altered GABA-related inhibitory function in neurodevelopmental disorders, and associated these changes with cognitive deficits in information processing (8, 9). Reduced GABA levels and function may similarly account for disrupted cognitive-emotional processes in MDD (10, 11). For instance, functional neuroimaging identified MDD-related hyperactivity in the default mode network ( DMN ), a set of brain regions including the dorsolateral prefrontal cortex ( dlPFC ), posterior and anterior cingulate cortices ( ACC ), amygdala, and hippocampus (12, 13).…”

Section: Cognitive-emotional Disruption and Excitation-inhibition Balmentioning

confidence: 99%

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

Fee

Banasr

Sibille

2017

Biological Psychiatry

284

217

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The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely-tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BPD), anxiety disorders, and schizophrenia (SCZ). Specifically, nearly three decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that co-express the neuropeptide somatostatin (“SST cells/interneurons”). Advances in cell type-specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders, and specifically in MDD. We then focus on properties of the cortical microcircuit, wherein SST-positive GABA interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology, and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions.

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Section: Cognitive-emotional Disruption and Excitation-inhibition Balmentioning

confidence: 99%

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

Fee

Banasr

Sibille

2017

Biological Psychiatry

284

217

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“…However, accumulating evidence suggests that loss of intra-cortical GABAergic transmission and consequent imbalances in excitatory and/or inhibitory neurotransmission in the PFC contribute to the etiology of stress-related psychiatric disorders (12). C linical studies have reported reduced GABA levels in the frontal cortex of depressed individuals as compared to healthy humans.…”

Section: Pfc Gaba Dysfunction In Stress and Depressionmentioning

confidence: 99%

“…However, multiple labs have contributed to the understanding GABAergic regulation in other brain regions in depression and other related disorders (12, 29). …”

Section: Pfc Gaba Dysfunction In Stress and Depressionmentioning

confidence: 99%

Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression

Ghosal

Hare

Duman

2017

Current Opinion in Behavioral Sciences

160

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Psychiatric diseases, notably major depression, are associated with imbalance of excitatory and inhibitory neurotransmission within the prefrontal cortex (PFC) and related limbic brain circuitry. In many cases these illnesses are precipitated or exacerbated by chronic stress, which also alters excitatory and inhibitory neurotransmitter systems. Notably, exposure to repeated uncontrollable stress causes persistent changes in the synaptic integrity and function of the principal glutamatergic excitatory neurons in the PFC, characterized by neuronal atrophy and loss of synaptic connections. This can lead to dysfunction of the PFC circuitry that is necessary for execution of adaptive behavioral responses. In addition, an emerging literature shows that chronic stress also causes extensive alteration of GABAergic inhibitory circuits in the PFC, leading to the hypothesis that inhibitory neurotransmitter deficits contribute to changes in PFC neuronal excitability and cognitive impairments. Here we review evidence in rodents and human, which point to the mechanisms underlying stress-induced alterations of GABA transmission in the PFC, and its relevance to circuit dysfunction in mood and stress related disorders. These findings suggest that alterations of GABA interneurons and inhibitory neurotransmission play a causal role in the development of stress-related neurobiological illness, and could identify a new line of GABA related therapeutic targets.

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“…Altered levels and signaling of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, is frequently reported in depression [1, 2], anxiety disorder [3], normal ageing [4], and neurodegenerative disorders, including Alzheimer’s disease [5], and in multiple brain regions including the prefrontal cortex [6] and anterior cingulate cortex [7]. Recent studies showed that such reductions of GABA levels in the human brain are associated with cognitive impairments in an age-dependent manner [8] and are further worsened during older age [9].…”

Section: Introductionmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

124

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Altered gamma-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging, and neurodegenerative disorders and reduced function of GABA interneurons is associated with both mood and cognitive symptoms. Benzodiazepines (BZ) have broad anxiolytic, but also sedative, anticonvulsant and amnesic effects, due to nonspecific GABA-A receptor (GABAA-R) targeting. Varying the profile of activity of BZs at GABAA-Rs is predicted to uncover additional therapeutic potential. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands and tested them for positive allosteric modulation at multiple α-GABAA-R (α-positive allosteric modulators), pharmacokinetic properties, as well as anxiolytic and antidepressant activities in adult mice. Efficacy at reversing stress-induced or age-related working memory deficits was assessed using a spontaneous alternation task. Diazepam (DZP) was used as a control. Three ligands (GL-II-73, GL-II-74, and GL-II-75) demonstrated adequate brain penetration and showed predictive anxiolytic and antidepressant efficacies. GL-II-73 and GL-II-75 significantly reversed stress-induced and age-related working memory deficits. In contrast, DZP displayed anxiolytic but no antidepressant effects or effects on working memory. We demonstrate distinct profiles of anxiolytic, antidepressant, and/or pro-cognitive activities of newly designed IBZD amide ligands, suggesting novel therapeutic potential for IBZD derivatives in depression and aging.

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GABAergic Control of Depression-Related Brain States

Cited by 125 publications

References 323 publications

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

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