Krešimir Krnjević (1927–2021) and GABAergic inhibition: a lifetime dedication

2021 ◽  
pp. 1-4
Author(s):  
Yehezkel Ben-Ari ◽  
Enrico Cherubini ◽  
Massimo Avoli
Keyword(s):  
Canadian Journal ◽  
Chief Editor ◽  
Aminobutyric Acid ◽  
Gabaergic Inhibition ◽  
Inhibitory Neurotransmitter ◽  
Neuroscience Research ◽  
Personal Interactions ◽  
The Brain ◽  
Made In

After over seven decades of neuroscience research, it is now well established that γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. In this paper dedicated to Krešimir Krnjević (1927–2021), a pioneer and leader in neuroscience, we briefly highlight the fundamental contributions he made in identifying GABA as an inhibitory neurotransmitter in the brain and our personal interactions with him. Of note, between 1972 and 1978 Dr. Krnjević was a highly reputed Chief Editor of the Canadian Journal of Physiology and Pharmacology.

scholarly journals The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy

2021 ◽  
Vol 22 (6) ◽  
pp. 3149
Author(s):  
Hye Yun Kim ◽  
Pann-Ghill Suh ◽  
Jae-Ick Kim
Keyword(s):  
Phospholipase C ◽  
Intracellular Signaling ◽  
Neuronal Development ◽  
Gabaergic Inhibition ◽  
Inhibitory Neurotransmitter ◽  
Intracellular Signaling Pathway ◽  
Key Enzyme ◽  
The Central Nervous System ◽  
Neuronal Functions ◽  
The Brain

Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy.

scholarly journals Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice

2015 ◽  
Vol 113 (9) ◽  
pp. 3421-3431 ◽  
Author(s):  
H. Romo-Parra ◽  
P. Blaesse ◽  
L. Sosulina ◽  
H.-C. Pape
Keyword(s):  
De Novo ◽  
Brain Regions ◽  
Network Activity ◽  
Aminobutyric Acid ◽  
Gabaergic Inhibition ◽  
Central Amygdala ◽  
Cognitive Behaviors ◽  
Excitatory Neurotransmission ◽  
Inhibitory Signaling ◽  
The Brain

Neurosteroids are formed de novo in the brain and can modulate both inhibitory and excitatory neurotransmission. Recent evidence suggests that the anxiolytic effects of neurosteroids are mediated by the amygdala, a key structure for emotional and cognitive behaviors. Tonic inhibitory signaling via extrasynaptic type A γ-aminobutyric acid receptors (GABAARs) is known to be crucially involved in regulating network activity in various brain regions including subdivisions of the amygdala. Here we provide evidence for the existence of tonic GABAergic inhibition generated by the activation of δ-subunit-containing GABAARs in neurons of the lateral section of the mouse central amygdala (CeAl). Furthermore, we show that neurosteroids play an important role in the modulation of tonic GABAergic inhibition in the CeAl. Taken together, these findings provide new mechanistic insights into the effects of pharmacologically relevant neurosteroids in the amygdala and might be extrapolated to the regulation of anxiety.

The GABA system and addiction

2018 ◽  
Author(s):  
David J. Nutt ◽  
Liam J. Nestor
Keyword(s):  
Potential Role ◽  
Abuse Liability ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Substance Addiction ◽  
Inhibitory Neurotransmitter ◽  
Gaba System ◽  
Clinical Potential ◽  
The Brain

Research points to the potential role of gamma-aminobutyric acid (GABA) in substance addiction. GABA is the major inhibitory neurotransmitter in the brain. Disturbances in the GABA system may predate substance abuse and addiction, whereby its efficacy to modulate other neurotransmitter systems (e.g. dopamine) strongly implicated in substance addiction behaviours is impaired. There are a number of addictive substances that boost GABA functioning, however, such as alcohol and benzodiazepines. Medications that boost the availability of GABA or mimic its effects at receptors may possess some clinical potential in treating addiction, but also have abuse liability.

Synapses, networks, brain development – funding basic neuroscience research in Germany by the Schram Foundation

Neuroforum ◽  
2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Dorothea Schulte ◽  
Christian Rosenmund ◽  
Eckart D. Gundelfinger
Keyword(s):  
Brain Function ◽  
Basic Research ◽  
Academic Level ◽  
Neuroscience Research ◽  
Scientific Exchange ◽  
Deep Conviction ◽  
The Many ◽  
The Individual ◽  
The Brain ◽  
Made In

AbstractResearch driven solely by curiosity and the desire to understand fundamental principles of brain function. The freedom to address important questions with bold, sometimes risky experiments. A platform for open scientific exchange and discussions at highest academic level to provide new impulses to the field. And a growing number of scientists who share the passion for neuroscience and who join forces to tackle some of the big mysteries that surround the brain. These visions together with the deep conviction that basic research is the fundament needed for any progress in applied science motivated Dr. Armin Schram to create the foundation that carries his name. They are also the ideals that the foundation still pursues, and to date, 26 research proposals designed by individual researchers or small teams have been, or are, supported in this spirit. Here, we introduce the reader to the individual scientists who were awarded grants by the Schram Foundation over the years, highlight some of the many discoveries made in the course of their studies and list some of the key publications that arose from this work.

scholarly journals Brain neurosteroids are natural anxiolytics targeting α2 subunit γ-aminobutyric acid type-A receptors

2018 ◽  
Author(s):  
Elizabeth J Durkin ◽  
Laurenz Muessig ◽  
Tanja Herlt ◽  
Michael J Lumb ◽  
Ryan Patel ◽  
...  
Keyword(s):  
Stress Hormones ◽  
Type A ◽  
Aminobutyric Acid ◽  
Anxiety And Depression ◽  
Neurotransmitter Receptor ◽  
Inhibitory Neurotransmitter ◽  
Naturally Occurring ◽  
Acid Type ◽  
The Brain

AbstractNeurosteroids are naturally-occurring molecules in the brain that modulate neurotransmission. They are physiologically important since disrupting their biosynthesis precipitates neurological disorders, such as anxiety and depression. The endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone are derived from sex and stress hormones respectively, and exhibit therapeutically-useful anxiolytic, analgesic, sedative, anticonvulsant and antidepressant properties. Their main target is the γ-aminobutyric acid type-A inhibitory neurotransmitter receptor (GABAAR), whose activation they potentiate. However, whether specific GABAAR isoforms and neural circuits differentially mediate endogenous neurosteroid effects is unknown. By creating a knock-in mouse that removes neurosteroid potentiation from α2-GABAAR subunits, we reveal that this isoform is a key target for neurosteroid modulation of phasic and tonic inhibition, and is essential for the anxiolytic role of endogenous neurosteroids, but not for their anti-depressant or analgesic properties. Overall, α2-GABAAR targeting neurosteroids may act as selective anxiolytics for the treatment of anxiety disorders, providing new therapeutic opportunities for drug development.

scholarly journals Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 530
Author(s):  
Oliviero Bruni ◽  
Luigi Ferini-Strambi ◽  
Elena Giacomoni ◽  
Paolo Pellegrino
Keyword(s):  
Gaba Receptors ◽  
Herbal Medicines ◽  
Well Being ◽  
Herbal Remedies ◽  
Gamma Aminobutyric Acid ◽  
Systematic Analysis ◽  
Inhibitory Neurotransmitter ◽  
Alternative Medicines ◽  
Molecular Components ◽  
The Brain

Sleep is an essential component of physical and emotional well-being, and lack, or disruption, of sleep due to insomnia is a highly prevalent problem. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Centuries-old herbal treatments, popular for their safety and effectiveness, include valerian, passionflower, lemon balm, lavender, and Californian poppy. These herbal medicines have been shown to reduce sleep latency and increase subjective and objective measures of sleep quality. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a major role in controlling different vigilance states. GABA receptors are the targets of many pharmacological treatments for insomnia, such as benzodiazepines. Here, we perform a systematic analysis of studies assessing the mechanisms of action of various herbal medicines on different subtypes of GABA receptors in the context of sleep control. Currently available evidence suggests that herbal extracts may exert some of their hypnotic and anxiolytic activity through interacting with GABA receptors and modulating GABAergic signaling in the brain, but their mechanism of action in the treatment of insomnia is not completely understood.

scholarly journals Molecular mechanisms of metabotropic GABAB receptor function

2021 ◽  
Vol 7 (22) ◽  
pp. eabg3362
Author(s):  
Hamidreza Shaye ◽  
Benjamin Stauch ◽  
Cornelius Gati ◽  
Vadim Cherezov
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Neurological Diseases ◽  
Activation Mechanism ◽  
Allosteric Modulators ◽  
Inhibitory Neurotransmitter ◽  
Therapeutic Drugs ◽  
G Protein Coupled ◽  
The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

Cerebrospinal fluid γ-aminobutyric acid levels in dogs with chronic portosystemic encephalopathy

1986 ◽  
Vol 71 (6) ◽  
pp. 749-753 ◽  
Author(s):  
J. E. Maddison ◽  
D. Yau ◽  
P. Stewart ◽  
G. C. Farrell
Keyword(s):  
Cerebrospinal Fluid ◽  
Aminobutyric Acid ◽  
Plasma Ammonia ◽  
Portosystemic Encephalopathy ◽  
Dog Model ◽  
Csf Levels ◽  
Neurological Features ◽  
The Brain ◽  
Biochemical Abnormalities

1. Cerebrospinal fluid (CSF) γ-aminobutyric acid (GABA) levels were measured in a dog model of spontaneous chronic portosystemic encephalopathy. 2. Dogs with congenital portacaval shunts (intra- or extra-hepatic) develop neurological features of abnormal psychomotor behaviour and depressed consciousness that are consistent with the symptoms of chronic portosystemic encephalopathy in humans. In the five dogs studied, plasma ammonia was elevated, as was CSF tryptophan, both usual biochemical abnormalities in portosystemic encephalopathy. 3. CSF levels of GABA in five dogs with portosystemic encephalopathy (100 ± 13 pmol/ml) were not significantly different from those in five control dogs (96 ± 14 pmol/ml). CSF levels of GABA were not altered after ammonia infusion. 4. If enhanced GABA-ergic neurotransmission, due to influx of gut-derived GABA into the brain, is responsible for the pathophysiology of chronic portosystemic encephalopathy in this model, it is not reflected by increased levels of GABA in CSF.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

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