The Curious Anti-Pathology of the Wld s Mutation: Paradoxical Postsynaptic Spine Growth Accompanies Delayed Presynaptic Wallerian Degeneration

Oswald Steward; Jennifer M Yonan; Paula M Falk

doi:10.3389/fnmol.2021.735919

The Curious Anti-Pathology of the Wld ^s Mutation: Paradoxical Postsynaptic Spine Growth Accompanies Delayed Presynaptic Wallerian Degeneration

Front Mol Neurosci. 2021 Sep 10:14:735919. doi: 10.3389/fnmol.2021.735919. eCollection 2021.

Authors

Oswald Steward^{1

2

3

4

5}, Jennifer M Yonan^{1

2}, Paula M Falk⁵

Affiliations

¹ Reeve-Irvine Research Center, University of California, Irvine, Irvine, CA, United States.
² Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA, United States.
³ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States.
⁴ Department of Neurosurgery, University of California, Irvine, Irvine, CA, United States.
⁵ Department of Neuroscience, University of Virginia, Charlottesville, VA, United States.

Abstract

The Wld ^s mutation, which arose spontaneously in C57Bl/6 mice, remarkably delays the onset of Wallerian degeneration of axons. This remarkable phenotype has transformed our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies. Although there are numerous studies of how the Wld ^s mutation affects axon degeneration, especially in the peripheral nervous system, less is known about how the mutation affects degeneration of CNS synapses. Here, using electron microscopy, we explore how the Wld ^s mutation affects synaptic terminal degeneration and withering and re-growth of dendritic spines on dentate granule cells following lesions of perforant path inputs from the entorhinal cortex. Our results reveal that substantial delays in the timing of synapse degeneration in Wld ^s mice are accompanied by paradoxical hypertrophy of spine heads with enlargement of post-synaptic membrane specializations (PSDs) and development of spinules. These increases in the complexity of spine morphology are similar to what is seen following induction of long-term potentiation (LTP). Robust and paradoxical spine growth suggests yet to be characterized signaling processes between amputated but non-degenerating axons and their postsynaptic targets.

Keywords: denervation; dentate gyrus; entorhinal cortex; nicotinamide adenyltransferase 1 (NMNAT1); perforant path; reinnervation; ubiquitination factor U4B.