A Siphon Hypothesis Goes Down the Tube
Monica R. Metea, Paulo Kofuji, and Eric A. Newman
(see pages 2468–2471)
So-called neurovascular coupling reflects local blood flow changes that accompany neuronal activity. Not only is this a homeostatic metabolic mechanism, but it also serves as the basis for functional brain imaging. The theory goes that glia cells siphon activity-generated extracellular potassium ions to glial endfeet abutting small blood vessels, leading to vessel relaxation. Not so, say Metea et al. in this week's Journal. In a rat retina preparation, light stimulation evoked vasodilation as did increases in extracellular potassium. However, long and large depolarizations of single astrocytes or Müller cells did not produce changes in arteriole diameter. In mice lacking Kir4.1, the potassium channel that is expressed at glial endfeet adjacent to arterioles, light-evoked vasodilation was similar to wild-type mice. If it's not potassium siphoning, what is it? The authors suggest that glial-derived arachidonic acid metabolites, known to contribute to vasomotor response, may be the culprit.
Presynaptic TrkB Signaling
Sonya Marshak, Angeliki Maria Nikolakopoulou, Ron Dirks, Gerard J. Martens, and Susana Cohen-Cory
(see pages 2444–2456)
“Is it pre- or postsynaptic?” used to be the battle cry for workers in the long-term potentiation field. Now it's a question for those studying TrkB. Signaling between brain-derived neurotrophic factor and its receptor TrkB contributes to the development of visual pathways. Marshak et al. made use of the alternatively spliced TrkB.T1, which lacks the intracellular kinase domain and thus can act as a dominant-negative inhibitor of TrkB signaling. The authors overexpressed a green fluorescent protein (GFP)–TrkB1.T1 fusion protein in their favorite presynaptic cells, Xenopus laevis retinal ganglion cells (RGCs). GFP–TrkB.T1 did not disrupt axon pathfinding to the tectum. However, time-lapse confocal microscopy in vivo revealed abnormal features in RGCs, including axons with immature growth cone-like morphology, reduced branching, increased motility, and less presynaptic specializations. Consistent with a cell-autonomous presynaptic site of action, these changes were not seen when GFP–TrkB.T1 was expressed in postsynaptic tectal neurons.
A CRF1 Antagonist as Treatment for Alcohol Dependence in Rats
Donald R. Gehlert, Andrea Cippitelli, Annika Thorsell, Anh Dzung Lê, Philip A. Hipskind, Chafiq Hamdouchi, Jianliang Lu, Erik J. Hembre, Jeffrey Cramer, Min Song, David McKinzie, Michelle Morin, Roberto Ciccocioppo, and Markus Heilig
(see pages 2718–2726)
Treating alcohol withdrawal is no fun for patient or caregiver, as any medical intern can attest. One promising treatment approach is based on dysregulation of the corticotropin-releasing hormone (CRF) system in alcohol dependence and withdrawal. CRF antagonists block the anxiogenic effects of alcohol withdrawal, but their potential therapeutic use has been limited by lack of appropriate compounds. This week, Gehlert et al. report on a CRF antagonist that may have the right stuff: it is orally active, penetrates into the brain, and has high affinity at CRF1 receptors. The compound 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) selectively inhibited binding at CRF1 receptors and CRF-mediated formation of cAMP. In alcohol-naive Wistar rats, MTIP reversed the anxiogenic-like effects of withdrawal from a single large dose of alcohol. In alcohol-dependent rats or rats genetically selected for high alcohol preference, a lower dose of MTIP blocked excessive self-administration.
Neurobiology of Disease
Paraquat-Induced Parkinsonism in the Fly
Anathbandhu Chaudhuri, Kevin Bowling, Christopher Funderburk, Hakeem Lawal, Arati Inamdar, Zhe Wang, and Janis M. O'Donnell
(see pages 2457–2467)
Recently identified genes account for only a small minority of Parkinson's disease, although genetic susceptibility and environmental factors presumably play a role in many other cases. This week, Chaudhuri et al. used Drosophila to examine the interplay between genes and the oxidative stress caused by exposure to the herbicide paraquat. They looked at heterozygous mutations in genes involved in dopamine (DA) biosynthesis: pale (ple), which encodes tyrosine hydroxylase (TH), and punch (Pu), which encodes GRP cyclohydrolase I (GTPCH), a synthesizing enzyme of the TH cofactor tetrahydrobiopterin (BH4). A third gene, Catecholamines up (Catsup) modifies GTPCH and TH to negatively regulate DA production. Paraquat ingestion by wild-type flies induced a PD-like behavioral phenotype, reduced life span, and loss of DA neurons. Surprisingly Catsup mutant flies, with their increased DA synthesis, withstood paraquat better than Pu and ple mutants with impaired DA synthesis, opposite the simplest version of a dopamine-induced oxidative stress hypothesis.