Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium dependence of somatodendritic dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was ∼20-fold greater than in cell body regions of the VTA or SNc. However, the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine tr...

The development of Schwann cells, which myelinate axons in the peripheral nervous system, is critically dependent on MEK/ERK signaling. While Ets-domain transcription factors ( Etv1 , Etv4 , Etv5 ) are downstream effectors of this pathway, only Etv1 has been specifically linked to Schwann cell development. Here, we examined the functions of Etv5 , which is expressed in Schwann cell precursors, neural crest cells and satellite glia, at embryonic stages and at low levels in mature Schwann cells. In hypomorphic Etv5tm1Kmm homozygous mutant mice, no overt defects in Schwann cell differentiation were observed at embryonic stages. To study the function of Etv5 in juvenile (postnatal days 21–30) and mature adult (6 month) mice, we generated Etv5 conditional knock-outs (cKOs) using a Sox10-Cre driver. In juvenile male Etv5 -cKO mice, Schwann cell numbers increased normally after a peripheral nerve crush injury, a response that was attenuated by 6 months. Transmission electron microscopy of the naive sciatic nerve ...

Myelin-associated inhibitors (MAIs) contribute to failed regeneration in the CNS. The intracellular signaling pathways through which MAIs block axonal repair remain largely unknown. Here, we report that the kinase GSK3β is directly phosphorylated and inactivated by MAIs, consequently regulating protein–protein interactions that are critical for myelin-dependent inhibition. Inhibition of GSK3β mimics the neurite outgrowth inhibitory effect of myelin. The inhibitory effects of GSK3β inhibitors and myelin are not additive indicating that GSK3β is a major effector of MAIs. Consistent with this, overexpression of GSK3β attenuates myelin inhibition. MAI-dependent phosphorylation and inactivation of GSK3β regulate phosphorylation of CRMP4, a cytosolic regulator of myelin inhibition, and its ability to complex with RhoA. Introduction of a CRMP4 antagonist attenuates the neurite outgrowth inhibitory properties of GSK3β inhibitors. We describe the first example of GSK3β inactivation in response to inhibitory ligands...

In the developing nervous system, projection neurons extend axons tipped with motile growth cones that are responsible for navigating to their appropriate targets while avoiding inappropriate targets. In chicks and mammals, axons use a complex strategy called delayed interstitial branching to

Following transection of the cervical sympathetic trunk (CST), we have previously reported robust glial cell plasticity in the intermediolateral (IML) cell column of the spinal cord in close proximity to the injured parent cell bodies. At 7 days followi...

Interneurons act on principal neurons to pattern excitatory output allowing for neuronal synchronization and maintenance of homeostatic rhythms. Changes in excitatory patterning due to disruptions in inhibitory signaling are thought to be mechanistic in...

Cholinergic signaling has been recently implicated in myelination and as a promising target for demyelinating disorders. Despite established roles as a major neurotransmitter and source of choline metabolite, the contribution of acetylcholine (ACh) to o...

Propriospinal neurons can relay functional information past incomplete spinal cord injuries (SCI) and are good candidates to target for restoring neural connectivity across anatomically complete SCI. Propriospinal neurons do not regrow spontaneously acr...

Disease and injury to the central nervous system can result in severe and permanent loss of function and a lifetime of disability. With dramatic effects on health, economics and quality of life, new advances in regenerative medicine are urgently needed....

Axon degeneration accompanying CNS injury or disease typically results in permanent loss of function in human patients. This is largely due to an inability of mammals to reinitiate axon growth in adult CNS neurons. Mammalian optic nerve injury models ha...