Expression of GABAA receptor α1 subunit mRNA and protein in rat neocortex following photothrombotic infarction

Kharlamov, Elena A.; Downey, Kathy L.; Jukkola, Peter; Grayson, Dennis R.; Kelly, Kenneth G.

doi:10.1016/j.brainres.2008.02.070

Cited by 25 publications

(14 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In animal models, expression of GABA A receptor subunits shows a complex layer- and time-specific regulation after stroke. GABA A receptors generally decrease in perilesional cortical areas53270777879. Conversely, one recent report80 has shown that α1 subunit expression is increased in layer 5 after stroke and its activation using zolpidem improves recovery.…”

Section: Discussionmentioning

confidence: 99%

Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

Alia

Spalletti

Lai

et al. 2016

Sci Rep

View full text Add to dashboard Cite

A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. The GABAergic system is one of the key modulators of neuronal plasticity, and plays an important role in the control of “critical periods” during brain development. Here, we report a key role for GABAergic inhibition in functional restoration following ischemia in the adult mouse forelimb motor cortex. After stroke, the majority of cortical sites in peri-infarct areas evoked simultaneous movements of forelimb, hindlimb and tail, consistent with a loss of inhibitory signalling. Accordingly, we found a delayed decrease in several GABAergic markers that accompanied cortical reorganization. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAA receptor function. We found that hampering GABAA signalling led to significant restoration of function in general motor tests (i.e., gridwalk and pellet reaching tasks), with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. These data demonstrate a key role for GABAergic inhibition in limiting motor improvements after cortical stroke.

show abstract

Section: Discussionmentioning

confidence: 99%

Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

Alia

Spalletti

Lai

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Binary α1β3 receptors that are positively modulated by zolpidem may also have significant clinical effects in a number of neurological conditions where the ratio and location of various GABA receptor subunits are altered, for example, stroke 52 53 54 , or epilepsy 55 56 . Under these conditions, dramatic changes are occurring in the brain.…”

Section: Discussionmentioning

confidence: 99%

Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface

Has

Absalom

Nieuwenhuijzen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Zolpidem is not a typical GABAA receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABAA receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn2+. At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target.

show abstract

“…Results were standardized and presented as percentage change from the control value. Signals obtained in the same membrane but area different than bands were subtracted for background correction (Kharlamov et al 2008; Leung et al 2002). …”

Section: Methodsmentioning

confidence: 99%

Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex

Wabno

Hess

2012

J Neural Transm

View full text Add to dashboard Cite

Alterations in the functions of brain gamma-aminobutyric acid (GABA) inhibitory system and a distortion in the balance between excitatory and inhibitory synaptic transmission have been hypothesized to be possible causes of mood disorders. Experimental evidence points to modifications of GABAergic transmission as a result of prolonged treatment with antidepressant drugs, however, the influence of the tricyclic antidepressant imipramine on inhibitory synaptic transmission in the rat cerebral cortex has not yet been investigated. Therefore, in the present study the effects of single and repeated administration of imipramine were evaluated ex vivo in slices of the rat frontal cortex using electrophysiological approach. In slices prepared 2 days after the last drug administration from animals receiving imipramine for 14 days (dose 10 mg/kg p.o., twice daily) the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from layer II/III pyramidal neurons was decreased, while the mean amplitude of sIPSCs was increased. These effects were absent in slices obtained from rats which received imipramine once. Application of N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN 082), a selective mGluR7 allosteric agonist, to the slice incubation medium resulted in a decrease in the mean frequency of sIPSCs in preparations obtained from repeated imipramine-treated animals, in contrast to slices originating from control rats where no AMN 082-induced effects were observed. Repeated imipramine treatment reduced protein density levels of the three tested GABAA receptor subunits: α1, β2 and γ2. These data indicate that repeated treatment of normal rats with imipramine results in a modification of the release mechanism of GABA from presynaptic terminals and its modulation by mGluR7 receptors as well as in an alteration in GABAA receptor subunit protein levels in the rat cerebral cortex.

show abstract

Expression of GABAA receptor α1 subunit mRNA and protein in rat neocortex following photothrombotic infarction

Cited by 25 publications

References 63 publications

Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface

Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex

Contact Info

Product

Resources

About