Advertisement

Topics

Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke.

Summary of "Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke."

Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage-the peri-infarct zone-is critical for rehabilitation, as it shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important for the development of new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA(A) receptors and is caused by an impairment in GABA (γ-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for α5-subunit-containing extrasynaptic GABA(A) receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5- or δ-subunit-containing GABA(A) receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A) receptor function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.

Affiliation

[1] Department of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA [2] These authors contributed equally to this work. [3] Present address: Departments of Psychology and Anatomy and

Journal Details

This article was published in the following journal.

Name: Nature
ISSN: 1476-4687
Pages: 305-9

Links

DeepDyve research library

PubMed Articles [22436 Associated PubMed Articles listed on BioPortfolio]

Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke ...

Sensitivity of GABAergic Tonic Currents to Acute Ethanol in Cerebellar Granule Neurons is Not Age- or δ Subunit-Dependent in Developing Rats.

The age of first exposure to ethanol (EtOH), as well as reduced sensitivity to its motor-impairing effects, are associated with a future predisposition to abuse EtOH. In adolescence, acute EtOH potent...

A pharmacological assessment of agonists and modulators at α4β2γ2 and α4β2δ GABAA receptors: The challenge in comparing apples with oranges.

Extrasynaptically located γ-aminobutyric acid (GABA) receptors type A are often characterized by the presence of a δ subunit in the receptor complex. δ-containing receptors respond to low ambient c...

Involvement of opioid and gaba systems in the ventrolateral periaqueductal gray on analgesia associated with tonic immobility.

Ventrolateral periaqueductal gray (VL-PAG) contains key neuronal circuits related to the analgesic effect involved in integrated defensive behaviors such as immobility response (IR). The latter is cha...

γ-Aminobutyric acid addition alleviates ammonium toxicity by limiting ammonium accumulation in rice (Oryza sativa) seedlings.

Excessive use of nitrogen (N) fertilizer has increased ammonium (NH4 (+) ) accumulation in many paddy soils to levels that reduce rice vegetative biomass and yield. Based on studies of NH4 (+) toxicit...

Clinical Trials [4633 Associated Clinical Trials listed on BioPortfolio]

Effectiveness of GABA Agonists in Reducing the Reinforcing Effects of Cocaine

Cocaine abuse continues to represent a significant public-health concern. Cocaine likely creates its addictive effects by increasing levels of dopamine, a chemical found in the brain. GABA...

tDCS Effects on GABA Concentration and Brain Functional Connectivity in Young Adults

The aim of this study is to investigate whether anodal tDCS over the left M1 leads to a decrease of GABA concentration and alterations of functional brain connectivity in younger people, c...

Impact of GABA-Enhancing Agents on Cortical GABA Concentrations Across the Menstrual Cycle in Women

The goal of this series of challenge studies is to examine the impact of menstrual cycle phase on cortical GABA response to administration of agents with either direct (benzodiazepines) or...

Methylphenidate on Intracortical Inhibition in Methamphetamine Abusers Attention Deficit Hyperactivity Disorder (ADHD)

Previous studies using transcranial magnetic stimulation (TMS) with paired pulse protocols have shown that a conditioning TMS pulse applied to the human motor cortex changes the excitabili...

tDCS Effects on GABA Concentration and Brain Functional Connectivity in Older Adults of Retirement Age

The aim of this study is to investigate whether anodal tDCS over the left M1 leads to a decrease of GABA concentration and alterations of functional brain connectivity in older people, com...

Medical and Biotech [MESH] Definitions

Drugs that bind to but do not activate GABA-A RECEPTORS thereby blocking the actions of endogenous or exogenous GABA-A RECEPTOR AGONISTS.

Drugs that bind to but do not activate GABA-B RECEPTORS thereby blocking the actions of endogenous or exogenous GABA-B RECEPTOR AGONISTS.

Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and influence cells via interactions with G-proteins. GABA-B receptors are pharmacologically characterized by their insensitivity to the blocker bicuculline and sensitivity to the agonist L-baclofen. They are found both presynaptically and postsynaptically, and act variously by inhibition of adenylate cyclase, activation of phospholipase A2, activation of potassium channels, and inactivation of voltage-activated calcium channels.

Excessive winking; tonic or clonic spasm of the orbicularis oculi muscle.

The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activa

Quick Search
Advertisement
 


DeepDyve research library

Relevant Topics

Stroke - Cerebrovascular Disease (CVA)
A stroke is a serious medical condition that occurs when the blood supply to part of the brain is cut off. Strokes are a medical emergency and prompt treatment is essential because the sooner a person receives treatment for a stroke, the less damage is ...

Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...

Alzheimer's Disease
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase  'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...


Searches Linking to this Article