This Week in The Journal
Cellular/Molecular
WRP Facilitates Filopodia Protrusion
Benjamin R. Carlson, Krissey E. Lloyd, Allison Kruszewski, Il-Hwan Kim, Ramona M. Rodriguiz, et al.
(see pages 2447–2460)
Deformation of the plasma membrane—an early event in endocytosis and protrusion—is often produced by proteins containing BAR domains. These domains form curved structures that interact electrostatically with membrane lipids, causing the membrane to curve. Many such proteins also interact with proteins involved in regulation of actin polymerization, and thus they help to coordinate cytoskeletal and membrane dynamics. WAVE1-associated Rac-activating protein (WRP) interacts with proteins that facilitate actin remodeling and has an inverse BAR domain, suggesting it causes membrane protrusion. Carlson et al. found that in cultured neurons, WRP was localized to dendritic filopodia and in buds along dendrites from which filopodia later emerged. Overexpression of WRP increased filopodia density, whereas knock-out reduced filopodia density in cultures and reduced the percentage of mature-looking spines in vivo. Loss of WRP impaired performance on several long-term memory tasks, which may explain why WRP mutation has been linked to mental retardation in humans.
Images taken at times indicated show a filopodium (arrows) that emerged from a dendritic bud in which WRP (green) was concentrated. See the article by Carlson et al. for details.
Development/Plasticity/Repair
VTA Projections to Motor Cortex Are Required for Motor Learning
Jonas A. Hosp, Ana Pekanovic, Mengia S. Rioult-Pedotti, and Andreas R. Luft
(see pages 2481–2487)
The largest populations of dopaminergic neurons in the brain are in the substantia nigra pars compacta and ventral tegmental area (VTA). The former project to dorsolateral striatum and the caudate nucleus and regulate voluntary movements and posture, whereas the latter project to ventral striatum and prefrontal cortex and are involved in reward, emotion, and cognition. Dopaminergic terminals are also found in the primary motor cortex (M1), and Hosp et al. show that in rats ∼70% of these terminals arise in the ipsilateral VTA, with the remainder coming from substantia nigra or contralateral VTA. Neurotoxic lesions of VTA impaired rats' ability to learn a reach-and-grasp task, but did not affect the performance of the task if it was learned before VTA neurons were destroyed. The ability to learn the task was partially restored when a dopamine precursor was injected into M1, suggesting that VTA dopaminergic projections to M1 are required for motor learning.
Behavioral/Systems/Cognitive
GABA Levels Are Low in Pons during REM Sleep
Giancarlo Vanini, Bradley L. Wathen, Ralph Lydic, and Helen A. Baghdoyan
(see pages 2649–2656)
Transitions between sleep states and wakefulness are driven by interactions among several brain regions, including hypothalamus, preoptic area, and pontine reticular formation (PRF). The onset of rapid eye movement (REM) sleep is thought to be triggered by activation of dorsolateral pontine REM-on neurons, which are tonically inhibited during non-REM sleep and wakefulness by REM-off neurons that reside in PRF and other brainstem regions. Activating GABA receptors in PRF reduces the amount of time spent in sleep, whereas inhibiting GABA receptor activation increases sleep. This strongly suggests that GABA acts in the PRF to regulate sleep. Vanini et al. strengthen this hypothesis by using microdialysis to measure extracellular GABA levels in cat PRF over several hours, including sleep and wake states. GABA levels were significantly lower during REM sleep than during non-REM sleep or wakefulness. Moreover, an acetylcholinesterase inhibitor that induces REM sleep also decreased GABA levels, suggesting it works by decreasing GABA release in the PRF.
Neurobiology of Disease
Molecular Tolerance to Ethanol Depends on Exposure Duration
Cristina Velázquez-Marrero, Patricia Wynne, Alexandra Bernardo, Stephanie Palacio, Gilles Martin, et al.
(see pages 2436–2446)
Ethanol produces its intoxicating effects by acting on multiple substrates. For example, ethanol potentiates GABA and glycine transmission and inhibits glutamate transmission. These effects are mediated by direct actions on receptor subtypes, modulation of receptor insertion or phosphorylation, and modulation of transmitter release. Ethanol might affect neurotransmitter release partly by regulating large-conductance calcium-activated voltage-gated potassium (BK) channels. Ethanol potentiates BK channels in some neurons and inhibits them in others. In naive rodent striatal medium spiny neurons, ethanol potentiates BK channels, but this effect decreases with prolonged exposure. This results partly from degradation of ethanol-sensitive BK channel splice variants and their replacement with ethanol-tolerant variants. Velázquez-Marrero et al. show that this effect depends on the duration of exposure: after a 6 h ethanol exposure, levels of ethanol-tolerant splice variants increased. This was reflected in BK channel properties, including increased calcium sensitivity, slower activation, and longer open and closed times. Such changes did not occur after shorter ethanol exposures.
