Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: March 12, 2019

Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated exposure to chronic stress. For decades, monoaminergic deficit hypothesis of depression provided conceptual framework understand pathophysiology MDD. However, accumulating evidence suggests MDD stress are associated with an imbalance excitation-inhibition (E:I) within PFC, generated inhibitory synaptic transmission onto principal glutamatergic neurons. patients chronically stressed animals show reduction GABA GAD67 levels brain, decreased expression GABAergic interneuron markers, GABAA GABAB receptor levels. Moreover, genetically modified deletion specific receptors subunits or function depressive-like behaviors. Here, we provide further supporting role cortical interneurons, mainly somatostatin- parvalbumin-expressing cells, required for optimal E:I balance PFC discuss how malfunction these cells result depression-related Finally, considering relatively low efficacy current available medications, review new fast-acting pharmacological approaches target system treat We conclude deficits neurotransmission resulting from compromise integrity neurocircuits development other stress-related disorders. Drugs establish targeting systems promising as antidepressants represent breakthrough strategies treatment depression.

Language: Английский

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Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders

Pharmacology & Therapeutics, Journal Year: 2019, Volume and Issue: 204, P. 107402 - 107402

Published: Aug. 27, 2019

Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need improved drug treatments. In this review an overview drugs being studied different phases clinical trials their potential treatment fear-, anxiety- trauma-related presented. One strategy followed development refining improving compounds interacting with existing anxiolytic targets, such as serotonergic prototypical GABAergic benzodiazepines. A more innovative approach involves search novel mechanisms action using growing knowledge base concerning relevant neurocircuitries neurobiological underlying pathological fear anxiety. The target systems evaluated include glutamate, endocannabinoid neuropeptide systems, well ion channels targets derived from phytochemicals. Examples promising candidates currently generalised disorder, social panic obsessive compulsive disorder or post-traumatic stress ketamine, riluzole, xenon one common pharmacological modulation glutamatergic neurotransmission, neurosteroid aloradine. Finally, D-cycloserine, MDMA, L-DOPA cannabinoids have shown efficacy enhancing fear-extinction learning humans. They are thus investigated augmentative speeding up long-term effectiveness exposure-based psychotherapy, which could render chronic dispensable many patients. These efforts indicative a rekindled interest renewed optimism discovery field, after decades relative stagnation.

Language: Английский

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Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

Trends in Pharmacological Sciences, Journal Year: 2019, Volume and Issue: 40(7), P. 464 - 481

Published: May 27, 2019

Language: Английский

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Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(1), P. 151 - 167

Published: April 28, 2020

Language: Английский

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Optical control of neuronal ion channels and receptors

Nature reviews. Neuroscience, Journal Year: 2019, Volume and Issue: 20(9), P. 514 - 532

Published: July 9, 2019

Language: Английский

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The Neurobiology of Fear Generalization

Frontiers in Behavioral Neuroscience, Journal Year: 2019, Volume and Issue: 12

Published: Jan. 15, 2019

The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, animal must select appropriate defensive response based on previous experiences are not identical, weighing cues contextual information may predict safety or danger. Like other aspects memory, mediated by the coordinated actions prefrontal, hippocampal, amygdalar, thalamic brain areas. In this review, we describe our current understanding behavioral, neural, genetic, biochemical mechanisms involved fear. Fear hallmark many anxiety stress-related disorders, while its emergence, severity, manifestation sex-dependent. Therefore, to improve dialogue between human studies as well accelerate development effective therapeutics, emphasize need examine both sex differences remote timescales rodent models.

Language: Английский

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GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease

Seminars in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 116, P. 146 - 159

Published: Feb. 9, 2021

In this review, we focus on the potential role of γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments humans, with a particular Alzheimer's disease (AD). Well-established animal models have shown that GABA plays central regulating and synchronizing neuronal signaling hippocampus, brain area critical for undergoes early significant morphologic functional changes course AD. Neuroimaging research humans has documented hyperactivity hippocampus losses resting state connectivity Default Mode Network, network itself prominently includes hippocampus-presaging decline individuals at-risk Apolipoprotein ε4, highest genetic risk factor AD, is associated GABAergic dysfunction models, humans. combination, these findings suggest may be linchpin complex factors eventually leads to principal clinical hallmark AD: loss. Here, will review current literature supporting hypothesis. First, molecular cellular basis its cognition. Next, report evidence dysregulations AD normal aging, both human studies. Finally, outline model based results neuroimaging studies which hippocampal tasks concurrent even preceding diagnosis, along modulate association.

Language: Английский

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GABA tone regulation and its cognitive functions in the brain

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(9), P. 523 - 539

Published: July 26, 2023

Language: Английский

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Gut liver brain axis in diseases: the implications for therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 6, 2023

Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract, liver, and nervous systems. In past few decades, breakthrough progress has been made in gut liver brain axis, mainly through understanding its formation mechanism increasing treatment strategies. this review, we discuss various complex networks including barrier permeability, hormones, microbial metabolites, vagus nerve, neurotransmitters, immunity, toxic β-amyloid (Aβ) metabolism, epigenetic regulation gut-liver-brain axis. Some therapies containing antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), polyphenols, low FODMAP diet nanotechnology application regulate Besides, some special treatments targeting gut-liver include farnesoid X receptor (FXR) agonists, takeda G protein-coupled 5 (TGR5) glucagon-like peptide-1 (GLP-1) antagonists fibroblast growth factor 19 (FGF19) analogs. Targeting gut-brain embraces cognitive behavioral therapy (CBT), antidepressants tryptophan metabolism-related therapies. liver-brain contains Aβ future, better interactions will promote development novel preventative strategies discovery precise therapeutic targets multiple diseases.

Language: Английский

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Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: June 26, 2023

The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) the inhibitory neurotransmitter in brain, working primarily via GABA

Language: Английский

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