The Unusual Response of Serotonergic Neurons after CNS Injury: Lack of Axonal Dieback and Enhanced Sprouting within the Inhibitory Environment of the Glial Scar

Abstract

Serotonergic neurons possess an enhanced ability to regenerate or sprout after many types of injury. To understand the mechanisms that underlie their unusual properties, we used a combinatorial approach comparing the behavior of serotonergic and cortical axon tips over time in the same injury environment in vivo and to growth-promoting or -inhibitory substrates in vitro. After a thermocoagulatory lesion in the rat frontoparietal cortex, callosal axons become dystrophic and die back. Serotonergic axons, however, persist within the lesion edge. At the third week post-injury, 5-HT+ axons sprout robustly. The lesion environment contains both growth-inhibitory chondroitin sulfate proteoglycans (CSPGs) and growth-promoting laminin. Transgenic mouse serotonergic neurons specifically labeled by enhanced yellow fluorescent protein under control of the Pet-1 promoter/enhancer (ePet-EYFP) or cortical neurons were cultured on low amounts of laminin +/− relatively high concentrations of the CSPG aggrecan. Serotonergic neurons extended considerably longer neurites than did cortical neurons on low laminin and exhibited a remarkably more active growth cone on low laminin plus aggrecan during time-lapse imaging than did cortical neurons. Chondroitinase ABC treatment of laminin/CSPG substrates resulted in significantly longer serotonergic but not cortical neurite lengths. This increased ability of serotonergic neurons to robustly grow on high amounts of CSPG may be partially due to significantly higher amounts of GAP-43 and/or β1 integrin than cortical neurons. Blocking β1 integrin decreased serotonergic and cortical outgrowth on laminin. Determining the mechanism by which serotonergic fibers persist and sprout after lesion could lead to therapeutic strategies for both stroke and spinal cord injury.

Differences in Callosal and Forniceal Diffusion between Patients with and without Postconcussive Migraine

“…23 Pilot studies of sumatriptan use in PTM have demonstrated efficacy in the mTBI population in the acute setting. 25,26 The FSHC and CC both express the 5-HT 1a receptor, 23,[27][28][29] for which serotonin is a partial agonist. Although quantitative use of DTI metrics in the clinical setting is currently limited by the lack of universally accepted normative data, demonstrating injured regions associated with PTM is the first step toward an individual diagnostic tool.…”

In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits

“…We hypothesized that axons that normally display a high rate of synaptic and branch remodelling, that is, from Layer (L) 6 cortical cells would more readily respond to a lesion than axons that are typically more stable, that is, thalamocortical axons (TCA) projecting to the upper layers of the cortex 8 . This intrinsically specified plasticity is reminiscent of the differences in regeneration between different axonal tracts following injury [9][10][11] .…”

In vivo single branch axotomy induces GAP-43–dependent sprouting and synaptic remodeling in cerebellar cortex

“…The ability of adult neurons of the CNS to regenerate their axons in response to injury is limited in many neuronal types depending on both intrinsic and extrinsic factors (3)(4)(5)(6)(7)(8). Axons in the CNS represent a challenging site for targeted manipulation and in vivo imaging, and little is known about their postlesional reactive plasticity and how this is regulated by molecular mediators.…”