The role of synchronous firing on the neural circuit development

In vertebrates, neurotrophic signaling plays an important role in neuronal development, neural circuit formation, and neuronal plasticity, but its evolutionary origin remains obscure. We found and validated nucleotide sequences encoding putative neurotrophic ligands (neurotrophin, NT) and receptors (Trk and p75) in two annelids,Platynereis dumerilii(Errantia) andCapitella teleta(Sedentaria, for which some sequences were found recently by Wilson, 2009). Predicted protein sequences and structures ofPlatynereisneurotrophic molecules reveal a high degree of conservation with the vertebrate counterparts; some amino acids signatures present in the annelid Trk sequences are absent in the basal chordate amphioxus, reflecting secondary loss in the cephalochordate lineage. In addition, expression analysis of NT, Trk, and p75 duringPlatynereisdevelopment by whole-mount mRNAin situhybridization supports a role of these molecules in nervous system and circuit development. These annelid data corroborate the hypothesis that the neurotrophic signaling and its involvement in shaping neural networks predate the protostome-deuterostome split and were present in bilaterian ancestors.

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Developmental synaptic regulator, TWEAK/Fn14 signaling, is a determinant of synaptic function in models of stroke and neurodegeneration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2001679118 ◽

2021 ◽

Vol 118 (6) ◽

pp. e2001679118

Author(s):

Dávid Nagy ◽

Katelin A. Ennis ◽

Ru Wei ◽

Susan C. Su ◽

Christopher A. Hinckley ◽

...

Keyword(s):

Synaptic Transmission ◽

Neural Circuit ◽

Hippocampal Slices ◽

Visual Development ◽

Synaptic Function ◽

Synaptic Physiology ◽

Mature Brain ◽

Circuit Development ◽

Basal Synaptic Transmission

Identifying molecular mediators of neural circuit development and/or function that contribute to circuit dysfunction when aberrantly reengaged in neurological disorders is of high importance. The role of the TWEAK/Fn14 pathway, which was recently reported to be a microglial/neuronal axis mediating synaptic refinement in experience-dependent visual development, has not been explored in synaptic function within the mature central nervous system. By combining electrophysiological and phosphoproteomic approaches, we show that TWEAK acutely dampens basal synaptic transmission and plasticity through neuronal Fn14 and impacts the phosphorylation state of pre- and postsynaptic proteins in adult mouse hippocampal slices. Importantly, this is relevant in two models featuring synaptic deficits. Blocking TWEAK/Fn14 signaling augments synaptic function in hippocampal slices from amyloid-beta–overexpressing mice. After stroke, genetic or pharmacological inhibition of TWEAK/Fn14 signaling augments basal synaptic transmission and normalizes plasticity. Our data support a glial/neuronal axis that critically modifies synaptic physiology and pathophysiology in different contexts in the mature brain and may be a therapeutic target for improving neurophysiological outcomes.

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