Cellular/Molecular
Single Cocaine Treatment Induces LTP-Like Changes in VTA
Emanuela Argilli, David R. Sibley, Robert C. Malenka, Pamela M. England, and Antonello Bonci
(see pages 9092–9100)
A single systemic dose of cocaine is sufficient to produce long-term potentiation (LTP) of glutamatergic synapses onto the reward-responsive dopaminergic neurons in the ventral tegmental area (VTA) of rats. This week, Argilli et al. demonstrate that this LTP is produced locally in the VTA and develops within 3 h after cocaine is applied briefly to cultured midbrain slices. Cocaine treatment prevented the development of spike-timing-dependent LTP, suggesting that the two use similar mechanisms. Indeed, both significantly increase AMPA receptor/NMDA receptor ratio (measured by whole-cell recordings) by causing translocation of high-conductance GluR1 glutamate receptors into the synapse, both require initial activation of NMDA receptors, and both require protein synthesis. Cocaine blocks dopamine transporters, and the resulting increase in extracellular dopamine is likely to contribute to LTP by binding to D5 receptors, because LTP was prevented by specific D1/D5 antagonists (but not D2 antagonists), was induced by D1/D5 agonists, and was absent in D5-null mice.
Development/Plasticity/Repair
RhoA Increases Axonal Branching
Soichiro Ohnami, Mitsuharu Endo, Satoshi Hirai, Naofumi Uesaka, Yumiko Hatanaka, Toshihide Yamashita, and Nobuhiko Yamamoto
(see pages 9117–9121)
The Rho family of small GTPases regulates morphology and movement in many cell types by regulating the actin cytoskeleton. Ohnami et al. report that RhoA contributes to activity-induced branching of horizontally growing axons in the upper layers of the cortex in rats. In organotypic slice cultures, increasing RhoA activity pharmacologically or by introducing (via electroporation) a constitutively active form increased the number of short branches of horizontal axons without affecting the number of long branches. Conversely, an inhibitor of RhoA-kinase (a downstream effector of RhoA) reduced branching. Daily live imaging revealed that constitutively active RhoA altered branch dynamics by increasing both elongation and elimination of axons. These data suggest that RhoA increases branch formation without affecting stabilization. To link RhoA to neuronal activity, the authors blocked activity with sodium-channel and glutamate-receptor blockers. These decreased the amount of active RhoA. Furthermore, introducing constitutively active RhoA increased branching when activity was blocked.
Behavioral/Systems/Cognitive
Melanin Concentrating Hormone Regulates Hypocretin Neurons
Yan Rao, Min Lu, Fei Ge, Donald J. Marsh, Su Qian, Alex Hanxiang Wang, Marina R. Picciotto, and Xiao-Bing Gao
(see pages 9101–9110)
The neuropeptides hypocretin (aka orexin) and melanin concentrating hormone (MCH) are secreted by different neurons in the hypothalamus. In addition to projecting broadly throughout the brain, hypocretin- and MCH-expressing neurons innervate each other. They regulate body functions such as wakefulness, food intake, and reward. Hypocretin and dopamine increase spike frequency in hypocretin neurons by enhancing glutamate release from presynaptic terminals, and hypocretin also depolarizes MCH neurons. But the effect of MCH on hypocretin neurons is unknown. To address this question, Rao et al. used MCH receptor-1 knock-out mice. The basal firing rate of hypocretin neurons was similar in mutant and wild-type mice, but hypocretin- and dopamine-induced increases in firing were greater in mutants. In addition, miniature EPSCs in hypocretin neurons were larger in mutant mice than in controls. The results suggest that MCH exerts an inhibitory effect on hypocretin neurons, acting as negative feedback that counteracts positive feedback produced by hypocretin.
Neurobiology of Disease
Status Epilepticus Triggers Functional Changes in Microglia
Elena Avignone, Lauriane Ulmann, Françoise Levavasseur, François Rassendren, and Etienne Audinat
(see pages 9133–9144)
Injured neurons and glia release ATP, which activates microglia via purinergic receptors, thus triggering migration, phagocytosis, and release of inflammatory mediators. Because identifying microglia in situ is difficult, little is known about the activation process in vivo. Avignone et al. used mice in which GFP was expressed specifically in microglia (enabling identification) to elucidate changes that occur in these cells after kainate-induced status epilepticus, a model of epilepsy. Within 3 h after kainate injection, inflammatory mediators increased in the hippocampus, and expression of a purinergic receptor that regulates phagocytosis was upregulated. By 48 h, levels of all microglial purinergic receptors were elevated—including P2Y12, which is downregulated in other injury models. In addition, activated microglia proliferated, grew larger, and extended thicker processes that extend more quickly toward a source of purinergic agonist than controls. Finally, whole-cell recordings in hippocampal slices revealed a voltage-activated potassium current in activated microglia that was not present in controls.
Purinergic receptors, including P2Y12 receptors (red), are upregulated in activated microglia cells (green) 48 h after status epilepticus (right) compared to controls (left). See the article by Avignone et al. for details.
