Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6272501 | Neuroscience | 2015 | 13 Pages |
Abstract
GABA (γ-amino-butyric acid) -mediated signaling is normally associated with synaptic inhibition due to ionotropic GABA receptors that gate an inward Clâ current, hyperpolarizing the membrane potential. However, there are also situations where ionotropic GABA receptors trigger a Clâ efflux that results in depolarization. The well-characterized central nervous system of the medicinal leech was used to study the functional significance of opposing effects of GABA at the synaptic circuit level. Specifically, we focused on synapses made by the nociceptive N cell and the non-nociceptive P (pressure) cell that converge onto a common postsynaptic target. It is already known that GABA hyperpolarizes the P cell, but depolarizes the N cell and that inhibition of ionotropic GABA receptors by bicuculline (BIC) has opposing effects on the synapses made by these two inputs; enhancing P cell synaptic transmission, but depressing N cell synapses. The goal of the present study was to determine whether the opposing effects of GABA were due to differences in Clâ homeostasis between the two presynaptic neurons. VU 0240551 (VU), an inhibitor of the Clâ exporter K-Cl co-transporter isoform 2 (KCC2), attenuated GABA-mediated hyperpolarization of the non-nociceptive afferent while bumetanide (BUM), an inhibitor of the Clâ importer Na-K-Cl co-transporter isoform 1 (NKCC1), reduced GABA-mediated depolarization of the nociceptive neuron. VU treatment also enhanced P cell synaptic signaling, similar to the previously observed effects of BIC and consistent with the idea that GABA inhibits synaptic signaling at the presynaptic level. BUM treatment depressed N cell synapses, again similar to what is observed following BIC treatment and suggests that GABA has an excitatory effect on these synapses. The opposing effects of GABA could also be observed at the behavioral level with BIC and VU increasing responsiveness to non-nociceptive stimulation while BIC and BUM decreased responsiveness to nociceptive stimulation. These findings demonstrate that distinct synaptic inputs within a shared neural circuit can be differentially modulated by GABA in a functionally relevant manner.
Keywords
BUMN-methyl-d-glucamineNMDGNKCC1KCC2ECLNEOPPRBICPPFHEPESchloride equilibrium potentialEGABABicuculline5-HT4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidDMSOEPSPγ-amino-butyric acidAChPotassium acetateAcetylcholinesynaptic transmissionBumetanideanalysis of varianceANOVApaired-pulse facilitationDimethyl sulfoxideSerotoninnociceptioninput resistancepaired-pulse ratioNeostigmineexcitatory post-synaptic potentialKacChlorideGABA
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Authors
Y. Wang, T. Summers, W. Peterson, E. Miiller, B.D. Burrell,