This Week in the Journal
Tonic GABAA Receptor Currents in the Thalamus
Delia Belelli, Dianne R. Peden, Thomas W. Rosahl, Keith A. Wafford, and Jeremy J. Lambert
(see pages 11513–11520)
David W. Cope, Stuart W. Hughes, and Vincenzo Crunelli
(see pages 11553–11563)
Several recent studies have reported "tonic" activation of extrasynaptic GABAA receptors containing the δ subunit. This week, two papers examined the action of tonic GABAA currents in the thalamus. Cope et al. report that most thalamocortical neurons of the dorsal lateral geniculate nucleus and ventrobasal (VB) complex, but not the nucleus reticularis, had tonic GABAA currents. Block of the tonic current caused cells to switch from low-threshold bursts of actions potentials to tonic firing. Belelli et al. also examined tonic GABAA current in VB cells using the hypnotic drug etomidate, which acts on 2 subunit-containing receptors. Activation of the tonic current in VB cells was associated with increases in the slow-wave activity characteristic of the sedative action of etomidate. The tonic current was suppressed in VB neurons in a transgenic mouse with etomidate-insensitive 2 subunits (2N265S). The latter results suggest that tonic GABAA current contributes to the rhythmic activity that underlies sleep.
Endogenous Neurosteroids and Inflammatory Pain
Pierrick Poisbeau, Christine Patte-Mensah, Anne Florence Keller, Michel Barrot, Jean-Didier Breton, Oliva Erendira Luis-Delgado, Marie José Freund-Mercier, Ayikoe Guy Mensah-Nyagan, and Rémy Schlichter
(see pages 11768–11776)
This week, Poisbeau et al. report that 3α,5α-reduced neurosteroids (5αNS) modulate inflammatory pain in the rat spinal cord. In dorsal horn neurons of lamina II, inhibition results both from fast-decaying glycine receptor-mediated IPSCs and slow-decaying GABAA receptor-mediated IPSCs. Exogenous application of 5αNS increased the duration of GABAA receptor-mediated miniature IPSCs and, by so doing, revealed mixed glycine/GABA miniature IPSCs. The authors found that a rapid increase in GABAA-mediated inhibition in lamina II after hindpaw injection of carageenan was prevented by finasteride (FIN), a blocker of 5αNS production. FIN had no effect in control adult rats, indicating that levels of endogenous 5aNS were not sufficient to alter basal synaptic inhibition. The inflammatory stimulus increased sensitivities to thermal and mechanical stimuli, but FIN delivery before inflammation reduced only thermal hyperalgesia. The upregulation of neurosteroids by peripheral inflammation provides support for separate thermal and mechanical pain processing pathways.
A Cubic Millimeter of Sweetness in the Accumbens
Susana Peciña and Kent C. Berridge
(see pages 11777–11786)
Sweets and opiate drugs have powerful reward properties, mediated by µ-opioid pathways in the medial shell of the nucleus accumbens. This week, Peciña and Berridge pinpoint the location at which µ-opioids contribute to hedonic impact. Because the µ-opioid agonist D-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO) triggers Fos transcription, the authors measured Fos plumes to see the area affected by DAMGO microinjections. Like humans, animals make visible orofacial gestures in response to foods they like or dislike. In the rodent subjects, rhythmic and lateral tongue protrusions were scored as "liking," whereas gapes and head shakes were scored as "disliking" (see figure). With oral infusion of a sugary solution, DAMGO injections doubled hedonic reactions in a cubic millimeter hotspot in the rostromedial shell of the Nacc. Aversive reactions to quinine were significantly reduced. In contrast, sites at which DAMGO increased food intake were spread throughout the medial shell.
Neurobiology of Disease
A immunotherapy and the blood–brain barrier
Rashid Deane, Abhay Sagare, Katie Hamm, Margaret Parisi, Barbra LaRue, Huang Guo, Zhenhua Wu, David M. Holtzman, and Berislav V. Zlokovic
(see pages 11495–11503)
Buildup of amyloid (A) peptide in the brain of patients with Alzheimer's disease (AD), and its potential clearance by immunotherapy, depends in part on the blood–brain barrier (BBB). Brain A levels are affected by influx, mediated by the receptor for advanced glycation end products (RAGE), and efflux, mediated by the low-density lipoprotein receptor-related protein 1 (LRP). This week, Deane et al. investigate how A-specific IgG immunotherapy promoted A clearance from brains of the AD mouse, APPsw+/–. The A-specific IgG 4G8 created a peripheral sink effect, lowering RAGE-mediated influx of A across the BBB and increasing LRP-mediated efflux, although the latter pathway became less effective with age. 4G8 also crossed the BBB to sequester A within the brain. Exit of the A–anti-A complex depended on the major histocompatibility complex class I-related neonatal Fc receptor (FcRn). Deletion of FcRn, but not loss of LRP, significantly reduced brain clearance of 4G8.