The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.

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Missense mutations in ATP1A3 encoding Na+,K+-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na+,K+-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na+,K+-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na+,K+-ATPase α3, including upon the K+ pore and predicted K+ binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na+,K+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.

Seventy‐two chemicals were tested for their mutagenic potential in the L5178Y tk+/− mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269‐278, 1975) and Clive et al. (Mutat Res 59:61‐108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 μg/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p‐benzoquinone dioxime, benzyl acetate, 2‐biphenylamine HCl, bis(2‐chloro‐1‐methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2‐chloroethanol, chlorothalonil, cytarabine‐HCl, p,p′‐DDE, diazinon, 2,6‐dichloro‐p‐phenylenediamine, N,N‐diethylthiourea, diglycidylresorcinol ether, 2,4‐dimethoxy aniline‐HCl, disperse yellow 3, endosulfan, 1,2‐epoxyhexa‐decane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4′‐methylenedianiline 2 HCl, methyl viologen, nickel sulfate‐6H2O, 4,4′‐oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6‐tetrachloro‐4‐nitro‐anisole, 1,1,1,2‐tetrachloroethane, trichlorfon, 2,4,6‐trichlorophenol, 2,4,5‐trimetho‐xybenzaldehyde, 1,1,3‐trimethyl‐2‐thiourea, 1‐vinyl‐3‐cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2‐biphenylamine‐HCl, 2‐chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2‐tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11‐aminoundecanoic acid, boric acid, 5‐chloro‐o‐toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2‐ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4‐sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4‐dichlorobenzene, phenol, succinic acid‐2,2‐dimethyl hydrazide, and toluene.

Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses.Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine.Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus.