GABA_BReceptors Are the First Target of Released GABA at Lamina I Inhibitory Synapses in the Adult Rat Spinal Cord

Abstract

We have previously provided functional evidence that glycine and GABA are contained in the same synaptic vesicles and coreleased at the same synapses in lamina I of the rat spinal dorsal horn. However, whereas both glycine receptors (GlyRs) and GABA(A) receptors (GABA(A)Rs) are expressed on the postsynaptic target, under certain conditions inhibitory events appeared to be mediated by GlyRs only. We therefore wanted to test whether GABA(B) receptors could be activated in conditions where GABA released was insufficient to activate GABA(A)Rs. Focal stimulation in the vicinity of visually identified lamina I neurons elicited monosynaptic IPSCs in the presence of ionotropic glutamate receptor antagonists. Pairs of stimuli were given at different interstimulus intervals (ISI), ranging from 25 ms to 1 s to study the depression of the second of evoked IPSCs (paired pulse depression; PPD). Maximal PPD of IPSCs was 60 +/- 14% (SE) (of the conditioning pulse amplitude), at ISI between 150 and 200 ms. PPD was observed with IPSCs evoked at stimulus intensities where they had no GABA(A)R component. PPD of small evoked IPSCs was not affected by the GABA(A)R antagonist bicuculline but significantly attenuated by 10-30 microM CGP52432, a specific GABA(B) receptor antagonist. These data indicate that, under conditions where GABA released is insufficient to affect postsynaptic GABA(A)Rs at lamina I inhibitory synapses, significant activation of presynaptic GABA(B) receptors can occur.

Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

“…Interestingly, our results suggest that RET+ dDH neurons mainly use glycine to communicate with other DH neurons (Figure 5E and data not shown) but use GABA to communicate with primary afferents (Figure S5N). Our results also suggest that GABA B receptors play important functions in presynaptic inhibition of superficial DH neurons (Figures 5M–N and S5N), which is consistent with their high expression in primary afferents and previous functional studies (Chery and De Koninck, 2000; Towers et al, 2000; Yang and Ma, 2011). Nevertheless, our results do not exclude a contribution of GABA A receptors in presynaptic inhibition.…”

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

“…GABA B receptors are also present presynaptically on GABAergic terminals and have been shown to reduce GABA/glycine corelease from spinal dorsal horn neurons. 56 This example of presynaptic inhibition differs from PAD, and instead involves G protein-dependent inhibition of calcium channels. From this, one can appreciate that blocking GABA B receptors could enhance fast synaptic inhibition.…”

Glycine and GABAA receptor subunits on Renshaw cells: Relationship with presynaptic neurotransmitters and postsynaptic gephyrin clusters

“…One possibility is that GABA coreleased with glycine can bind to GABA B autoreceptors and provide negative feedback control for glycine release (Jonas et al, 1998;Grudt and Henderson, 1998;Lim et al, 2000;Chery and De Koninck, 2000). Nevertheless, significant GABA and glycine postsynaptic inhibitory currents were detected in spinal motoneurons, in addition to presynaptic GABA control (Jonas et al, 1998).…”