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

13:13 EDT 26th April 2015 | BioPortfolio

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

PubMed Articles [21230 Associated PubMed Articles listed on BioPortfolio]

GABAB receptor-mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram-treated rats.

Norepinephrine (NE)-releasing neurons in the locus coeruleus (LC) provide NE to the forebrain. Their activity is believed to be a key factor regulating the wakefulness/arousal level of the brain. In t...

Modulation of the input-output function by gabaa receptor-mediated currents in rat oculomotor nucleus motoneurons.

The neuronal input-output function depends on recruitment threshold and gain of the firing frequency-current (f-I) relationship. These two parameters are positively correlated in ocular motoneurons (M...

Extrasynaptic α6 Subunit-Containing GABAA Receptors Modulate Excitability in Turtle Spinal Motoneurons.

Motoneurons are furnished with a vast repertoire of ionotropic and metabotropic receptors as well as ion channels responsible for maintaining the resting membrane potential and involved in the regulat...

Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity.

GABA transporters control extracellular GABA, which regulates the key aspects of neuronal and network behaviour. A prevailing view is that modest neuronal depolarization results in GABA transporter ty...

Phasic and Tonic Inhibition are Maintained Respectively by CaMKII and PKA in the Rat Visual Cortex.

Phasic and tonic γ-aminobutyric acidA (GABAA) receptor-mediated inhibition critically regulate neuronal information processing. As these two inhibitory modalities have distinctive features in their r...

Clinical Trials [3263 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...

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...

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...

Treatment Of Primary Generalized Tonic-Clonic Seizures With An Investigational New Drug

The purpose of this study is to evaluate the effectiveness and safety of an investigational new drug for supplemental therapy in subjects with primary generalized tonic-clonic (PGTC) seizu...

The Effects of Topiramate on Alcohol Use and Brain Gaba Concentrations in Alcohol Dependent Subjects

This investigation will assess the effectiveness of topiramate in reducing ethanol consumption by alcohol dependent subjects. It also will seek to establish whether topiramate can be safel...

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

Search BioPortfolio:
Loading
Advertisement

Relevant Topics

Neurology - Central Nervous System (CNS)
Latest News Clinical Trials Research Drugs Reports Corporate
Neurology is the branch of medicine concerned with nerves; both the central nervous system and the peripheral nervous system. This includes strokes and disorders affecting the brain aswell as spinal cord damage and peripheral neuropathies.The complexity ...

Alzheimer's Disease
Latest News Clinical Trials Research Drugs Reports Corporate
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...

Advertisement