Papers of the Week

GABAergic neurons and GABA receptors (GABARs) are critical elements of almost all neuronal circuits. Most GABARs of the CNS are heteropentameric ion channels composed of two α, two β and one γ subunit. These receptors serve as important drug targets for benzodiazepine (BDZ) site agonists, which potentiate the action of GABA at GABARs. Most GABAR classifications rely on the heterogeneity of the α subunit (α1 – α6) included in the receptor complex. Heterogeneity of the γ subunits (γ1 – γ3), which mediate synaptic clustering of GABARs and contribute, together with α subunits, to the benzodiazepine (BDZ) binding site, has gained less attention, mainly because γ2 subunits greatly outnumber the other γ subunits in most brain regions. Here, we have investigated a potential role of non-γ2 GABARs in neural circuits of the spinal dorsal horn, a key site of nociceptive processing. Female and male mice were studied. We demonstrate that besides γ2 subunits, γ1 subunits are significantly expressed in the spinal dorsal horn, especially in its superficial layers. Unlike global γ2 subunit deletion, which is lethal, spinal cord specific loss of γ2 subunits was well tolerated. GABAR clustering in the superficial dorsal horn remained largely unaffected and antihyperalgesic actions of HZ-166, a non-sedative BDZ site agonist, were partially retained. Our results thus suggest that the superficial dorsal horn harbors functionally relevant amounts of γ1 subunits that support the synaptic clustering of GABARs in this site. They further suggest that γ1 containing GABARs contribute to the spinal control of nociceptive information flow. Our results identify for the first time a CNS area (the spinal dorsal horn) in which atypical GABA receptors containing the γ1 subunit serve a physiological role in the synaptic clustering of GABA receptors. They also show that pharmacological modulation of γ1 GABA receptors by a non-sedative GABA receptor modulator alleviates chronic pain in neuropathic mice.