Biology subjects

Munch, A. E.

Publications and source records attributed to Munch, A. E..

3 recordsLinked to original sources

bioRxiv2023

Blocking Formation of Neurotoxic Reactive Astrocytes is Beneficial Following Stroke

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1 (IL1), and complement component 1q (C1q), together TIC. This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.

neuroscience↗

bioRxiv2023

Oligodendrocyte calcium signaling regulates myelin sheath morphology

Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length and thickness are regulated by neuronal activity and can precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation and remodeling is unknown. Here, we used genetic tools to attenuate oligodendrocyte calcium signaling during active myelination in the developing mouse CNS. Surprisingly, we found that genetic calcium attenuation did not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation caused striking myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduced actin filaments in oligodendrocytes, and an intact actin cytoskeleton was necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a novel cellular mechanism required for accurate CNS myelin formation and provides mechanistic insight into how oligodendrocytes may respond to neuronal activity to sculpt myelin sheaths throughout the nervous system.

neuroscience↗

bioRxiv2022

Schwann cells promote sensory neuron excitability during development

Excitability--the ability to fire action potentials--is a signature feature of neurons. How neurons become excitable during development, and whether excitability is an intrinsic property of neurons or requires signaling from glial cells, remain unclear. Here we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of voltage-gated sodium channels and fire action potential trains. Inactivating this signaling pathway specifically in Schwann cells selectively impairs the maturation of nociceptor and proprioceptor somatosensory neuron subtypes, leading to corresponding sensory defects in thermoception, inflammatory pain, and proprioception. Our studies thus reveal a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.

neuroscience↗