Methods for recording and measuring tonic GABAA receptor-mediated inhibition

Bright, Damian P.; Smart, Trevor G.

doi:10.3389/fncir.2013.00193

Cited by 58 publications

(59 citation statements)

References 128 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GABA-A mediated tonic conductances have been studied across several brain regions and in the cerebellum and olfactory bulb have been found to be important regulators of neuronal excitability in vivo . High affinity GABA-A receptors, containing α5 or δ subunits underlie these tonic conductances, which are typically measured as a change in holding current of the cell as well as a change in current noise (Bright and Smart, 2013). The most consistent finding across striatal regions was the presence of a larger density of tonic inward current in dMSNs from iMSN-Drd2KO mice (0.6 ± 0.1 pA/pF for Drd2 loxP/loxP vs. −1.0 ± 0.1 pA/pF for iMSN-Drd2KO; p = 0.002, n = 14–25; Figure 6a–c & S5,6).…”

Section: Resultsmentioning

confidence: 99%

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

Lemos

Friend

Kaplan

et al. 2016

Neuron

124

164

View full text Add to dashboard Cite

Summary Bradykinesia is a prominent phenotype of Parkinson’s disease, depression, and other neurological conditions. Disruption of dopamine transmission plays an important role but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson’s disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission.

show abstract

Section: Resultsmentioning

confidence: 99%

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

Lemos

Friend

Kaplan

et al. 2016

Neuron

124

164

View full text Add to dashboard Cite

show abstract

“…Ethanol is an agonist for GABA A receptors, which when activated function as a chloride specific ion channel (48). GABA A receptors have been found on macrophages and their activation has been shown to have anti-inflammatory effects (49).…”

Section: Resultsmentioning

confidence: 99%

Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation

Hoyt

Ather

Randall

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Immunosuppression is a major complication of alcoholism that contributes to increased rates of opportunistic infections and sepsis in alcoholics. The NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18, can be inhibited by ethanol and we sought to better understand the mechanism through which this occurs and whether chemically similar molecules exert comparable effects. We show that ethanol can specifically inhibit activation of the NLRP3 inflammasome, resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as diminished ASC speck formation, without affecting potassium efflux, in a mouse macrophage cell line (J774), mouse bone marrow derived dendritic cells, mouse neutrophils, and human PBMCs. The inhibitory effects on the Nlrp3 inflammasome were independent of GABAA receptor activation or NMDA receptor inhibition, but was associated with decreased oxidant production. Ethanol treatment markedly decreased cellular tyrosine phosphorylation, while administration of the tyrosine phosphatase inhibitor sodium orthovanadate prior to ethanol restored tyrosine phosphorylation and IL-1β secretion subsequent to ATP stimulation. Furthermore, sodium orthovanadate-induced phosphorylation of ASC Y144, necessary and sufficient for Nlrp3 inflammasome activation, and secretion of phosphorylated ASC, were inhibited by ethanol. Finally, multiple alcohol-containing organic compounds exerted inhibitory effects on the Nlrp3 inflammasome, whereas 2-methylbutane (isopentane), the analogous alkane of the potent inhibitor isoamyl alcohol (isopentanol), did not. Our results demonstrate that ethanol antagonizes the NLRP3 inflammasome at an apical event in its activation through the stimulation of protein tyrosine phosphatases, an effect shared by other short-chain alcohols.

show abstract

“…The standard deviation of the holding current, which is equivalent to the RMS noise (square root of the variance), was used to measure current noise. Changes in current noise before and after GABA A R blockade is a way to assess changes in the activity of open GABA A Rs (Bright and Smart 2013). The percent change in the standard deviation (SD) of the holding current was calculated by measuring the standard deviation in a section free of synaptic activity before and after GABA A R blockade.…”

Section: Methodsmentioning

confidence: 99%

GABAB receptors in maintenance of neocortical circuit function

Sebe

Looke-Stewart

Baraban

2014

Experimental Neurology

View full text Add to dashboard Cite

Activation of metabotropic GABAB receptors (GABABRs), which enhances tonic GABA current, substantially increases the frequency of spontaneous seizures. Despite these pro-epileptic consequences of GABABR activation, mice lacking functional GABAB receptors (GABAB1R KO mice) exhibit clonic and rare absence seizures. To examine these mice further, we recorded excitatory and inhibitory synaptic inputs and tonic GABA currents from Layer 2 neocortical pyramidal neurons of GABAB1R WT and KO mice (P30-40). Tonic current was increased while the frequency of synaptic inputs was unchanged in KO mice relative to WT littermates. The neocortical laminar distribution of interneuron subtypes derived from the medial ganglionic eminence (MGE) was also not statistically different in KO mice relative to WT while the number of calretinin-positive, caudal GEderived, cells in Layer 1 was reduced. Transplantation of MGE progenitors obtained from KO mice lacking functional GABAB1R did not increase tonic inhibition in the host brain above that of media-injected controls. Taken together, these results suggest a complex role for GABAB receptors in mediating neocortical circuit function.

show abstract

Methods for recording and measuring tonic GABAA receptor-mediated inhibition

Cited by 58 publications

References 128 publications

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation

GABAB receptors in maintenance of neocortical circuit function

Contact Info

Product

Resources

About