Abstract

The Wlds 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 Wlds 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 Wlds 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 Wlds 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.

Highlights

  • The remarkable phenotype of delayed Wallerian degeneration in mice carrying the Wlds mutation has dramatically revised our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies

  • Insights into mechanisms came from subsequent studies revealing that NMNAT2, a rapidly turning over protein related to NAD+ synthesizing enzyme nicotinamide adenyltransferase 1 (NMNAT1), is a natural survival factor for axons and that axonal delivery of the Wlds protein with enzymatically active NMNAT1 can substitute for NMNAT2 to maintain axonal NAD levels after injury and promote axonal survival [for a recent review, see (Coleman and Hoke, 2020)]

  • For the electron microscopic (EM) analysis, we selected cases in which the lesion destroyed most of the entorhinal cortex with little or no damage to the posterior hippocampus

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Summary

Introduction

The remarkable phenotype of delayed Wallerian degeneration in mice carrying the Wlds mutation has dramatically revised our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies. The dramatic survival of orphaned axons in Wlds mice motivated studies to identify and target the relevant molecular pathways to abrogate axonal degeneration in various neurodegenerative diseases (Fischer et al, 2005; Gillingwater et al, 2006; Coleman and Freeman, 2010). Insights into mechanisms came from subsequent studies revealing that NMNAT2, a rapidly turning over protein related to NMNAT1, is a natural survival factor for axons and that axonal delivery of the Wlds protein with enzymatically active NMNAT1 can substitute for NMNAT2 to maintain axonal NAD levels after injury and promote axonal survival [for a recent review, see (Coleman and Hoke, 2020)]

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