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bioRxiv · 10.64898/2025.12.18.695322

Myelin maintenance and addition regulate synaptic plasticity in the adult mouse cortex

Pepper, R. E.·Makowiecki, K.·Pitman, K. A.·Ricci, R. P.·Nicoli, A.·Nguyen, P. T.·Blizzard, C.·Emery, B.·Cullen, C. L.·Young, K.
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Abstract

Myelination of the developing central nervous system (CNS) increases action potential conduction velocity but can also act as a plasticity brake, limiting neurite reorganisation and synaptic plasticity. As myelination is a life-long process, the myelin laid down in development or adulthood could also affect synapse number or plasticity across the lifespan. We report that conditionally deleting the transcription factor, myelin regulatory factor (Myrf), to disrupt the myelin maintenance program in oligodendrocytes (OLs) from P57 (Plp-CreERT2 :: Myrf fl/fl mice), led to significant myelin loss and impaired action potential conduction and gross motor performance. By sparsely labelling layer V pyramidal neurons in the primary motor cortex, we could visualise the apical and basal dendrites and their excitatory post-synaptic dendritic spines and determined that spine density was normal in P57+60 Plp-CreERT2 :: Myrf fl/fl mice. However, a higher proportion of the dendritic spines were large, stable mushroom spines and generated larger amplitude miniature excitatory post-synaptic currents. These data indicate that the myelin maintenance program is critical for preserving neuron adaptability, homeostasis and glutamate sensitivity. When we instead prevented the addition of new OLs and myelin from P57, action potential conduction velocity and gross motor performance appeared normal. Spine density was also normal in Pdgfr-CreERTM :: Myrf fl/fl mice, however, spine morphology was changed along the basal dendrites of layer V M1 pyramidal neurons. At P117, the basal dendrites were frozen in a state that resembled P57 dendrites, as they retained a higher proportion of thin, plastic spines. These data suggest that adult myelination supports the life-long accumulation of stable spines within the basal but not apical dendritic compartment and have important implications for understanding dendritic plasticity rules in the motor circuit. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/695322v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1a7928org.highwire.dtl.DTLVardef@83e7borg.highwire.dtl.DTLVardef@13e1e14org.highwire.dtl.DTLVardef@128e2df_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAdult myelin maintenance regulates synaptic plasticity and neuron homeostasis C_LIO_LIExisting myelin regulates layer V pyramidal neuron glutamate sensitivity C_LIO_LIOligodendrocytes born in young adulthood undergo age-related loss C_LIO_LINew myelin stabilises synapses in the basal but not apical dendritic compartment C_LI eTOC blurbMyelin regulates axon branching, metabolism and action potential conduction speed. We report that myelin also preserves neuron adaptability, homeostasis and glutamate sensitivity in the adult motor cortex. Furthermore, new myelin allows the accumulation of stable synapse on basal but not apical layer V pyramidal neuron dendrites over time.

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Pepper, R. E., Makowiecki, K., Pitman, K. A., Ricci, R. P., Nicoli, A., Nguyen, P. T., Blizzard, C., Emery, B., Cullen, C. L., Young, K.. 2025-12-19. Myelin maintenance and addition regulate synaptic plasticity in the adult mouse cortex. https://doi.org/10.64898/2025.12.18.695322

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