This Week in The Journal

Cellular/Molecular

5-HT Directly Enhances ASIC3 Currents

Xiang Wang, Wei-Guang Li, Ye Yu, Xian Xiao, Jin Cheng, et al.

Tissue damage causes gradual acidosis and release of inflammatory mediators, both of which enhance pain responses. Acidosis depolarizes somatosensory neurons by opening acid-sensing ion channels (ASICs), particularly ASIC3. ASIC3-mediated currents are biphasic, consisting of a large transient current and a smaller, sustained response. The latter is likely to play a larger role during injury-induced acidosis, because the former desensitizes during gradual acidosis. Several inflammatory mediators increase ASIC expression, thus enhancing the effect of acidosis after tissue damage. Wang et al. have discovered that one of these inflammatory mediators, 5-HT, also enhances sustained ASIC currents via direct interaction with the channel. In mouse dorsal root ganglion neurons, 5-HT enhanced currents induced by gradual acidosis independently of classical 5-HT receptors and intracellular signaling cascades, likely by binding to the “nonproton ligand sensing” domain of ASIC3. Thus, 5-HT increased the number of action potentials induced by acidic solution. Additionally, injecting 5-HT along with mild acid into mouse paws prolonged the nocifensive licking response.

Development/Plasticity/Repair

Notch Allows Perineurial Cells to Exit the CNS

Laura A. Binari, Gwendolyn M. Lewis, and Sarah Kucenas

(see pages 4241–4252)

Motor nerves are encased by a continuous, protective sheath, the perineurium, composed of perineurial glial cells connected by tight junctions. Perineurial cells are generated in the CNS and migrate through motor axon exit points (MEPs) immediately following motor axon growth cones. Binari et al. found that, in zebrafish larvae, perineurial glial cells formed a continuous chain as they exited the CNS and migrated along motor nerves. Upon leaving the CNS, perineurial cells began to express Notch, which was downregulated when migration was finished. Blocking Notch signaling before perineurial glia exited the CNS prevented their exit: although leader cells extended filopodia through MEPs, their somata remained within the CNS, even after Notch signaling was restored. Blocking Notch signaling after perineurial cells exited the CNS did not impair migration, but it did inhibit the formation of the tight junctions between cells that characterize the mature perineurium. Fewer Schwann cells were present along peripheral nerves when Notch signaling was disrupted, suggesting that perineurial cells influence myelination.

Perineurial glial cells (green) exit the CNS (left) and migrate along motor root axons (red). See the article by Binari et al. for details.

Systems/Circuits

Swim CPG Drives Compensatory Eye Movements in Frogs

Géraldine von Uckermann, Didier Le Ray, Denis Combes, Hans Straka, and John Simmers

(see pages 4253–4264)

To maintain a stable image of the world during locomotion, animals move their eyes to compensate for self-generated movement. In terrestrial vertebrates, the head moves in three dimensions, and feedback from the vestibular system is thought to be essential for directing eye movements. But in swimming Xenopus tadpoles, head movements are restricted to the horizontal plane, and conjugate left–right rotation of the eyes, driven by input from the central pattern generator (CPG) that drives swimming, is sufficient to compensate for head movements. After metamorphosis, however, frogs swim by synchronously kicking their hindlegs, resulting in linear forward acceleration. von Uckermann et al. observed that both eyes rotated inward, non-conjugately, during forward movement. Correspondingly, medial rectus motor neurons, which rotate the eyes inward, were synchronously active in phase with hindlimb extensor motor neurons. This occurred in isolated brainstem/spinal cord preparations, in the absence of visual or vestibular feedback, suggesting that input from the swim CPG continues to instruct compensatory eye movements after metamorphosis.

Neurobiology of Disease

Microglia Phagocytose Cortical Neuron Precursors

Christopher L. Cunningham, Verónica Martínez-Cerdeño, and Stephen C. Noctor

(see pages 4216–4233)

Early in cortical development, neural precursor cells (NPCs) proliferate, generating a large pool of progenitors in the subventricular zone (SVZ). As development proceeds, the progenitor pool is exhausted, preventing excessive growth of the brain. The reduction of the progenitor pool is thought to result from a combination of symmetric cell divisions that produce two postmitotic neurons and NPC apoptosis. But Cunningham et al. suggest that microglia also limit the size of the progenitor pool. The number of microglia in developing rat and primate cortex increased as corticogenesis proceeded. Microglia were concentrated in two bands in the SVZ, where they contacted and engulfed NPCs. Notably, most of the targeted NPCs were mitotically active, and few appeared to be undergoing apoptosis. After corticogenesis was complete, microglia became evenly distributed throughout the cortex. Finally, increasing the proportion of M1-type microglia reduced NPC numbers, whereas increasing the proportion of M2-type microglia or selectively killing microglia in utero increased the number of NPCs and immature neurons.