Biology subjects

Pitman, K. A.

Publications and source records attributed to Pitman, K. A..

4 recordsLinked to original sources

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2024

Gluk4-containing kainate receptors regulate synaptic communication in the motor cortex and reduce axon degeneration in adult mice

Glutamate-gated kainate receptors comprising the Gluk4 subunit (encoded by Grik4) are highly expressed by neurons in the central nervous system. We report that Grik4 mRNA is widely expressed by neurons in the adult mouse motor cortex, where GluK4-containing kainate receptors account for [~]60% of the kainate evoked current in layer V pyramidal neurons. To elucidate their role in motor circuit regulation, we analysed the behaviour of mice that lacked the pore forming domain of the GluK4 subunit (Grik4-/-mice). Grik4-/- mice were hyperactive, had an abnormal gait, and impaired motor coordination. At postnatal day (P)60, layer V pyramidal neurons received fewer miniature excitatory post synaptic currents, had a reduced density of thin spines on their basal dendrites, and a reduced density of VGlut1 puncta at the soma, consistent with neurons receiving fewer excitatory synaptic connections. Grik4-/- mice also lost [~]44% of their callosal axons between P60 and P180 and the amplitude of the callosal compound action potential was reduced by [~]25-30%. RNA sequencing data support the capacity for Grik4 to modulate synaptic and neuroprotective signalling pathways.

neuroscience↗

bioRxiv2020

Low-density lipoprotein receptor-related protein 1 (LRP1) is a negative regulator of oligodendrocyte progenitor cell differentiation in the adult mouse brain.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a large, endocytic cell surface receptor that is highly expressed by oligodendrocyte progenitor cells (OPCs), and LRP1 expression is rapidly downregulated as OPCs differentiate into oligodendrocytes (OLs). We report that the conditional deletion of Lrp1 from adult mouse OPCs (Pdgfr-CreER :: Lrp1fl/fl) increases the number of new myelinating OLs added to brain, but that each new cell elaborates a normal quantity of myelin. OPC proliferation is also elevated following Lrp1 deletion in vivo, however, this is likely to be a secondary, homeostatic response to increased OPC differentiation, as our in vitro experiments show that LRP1 is a direct negative regulator of OPC differentiation, not proliferation. Deleting Lrp1 from adult OPCs also enhances remyelination, as cuprizone-induced lesions are smaller in Lrp1-deleted mice, and parenchymal OPCs produce a larger number of mature OLs. These data suggest that the selective blockade of LRP1 function on adult OPCs may enhance myelin repair in demyelinating diseases, such as multiple sclerosis.

neuroscience↗

bioRxiv2019

Myelin and nodal plasticity modulate action potential conduction in the adult mouse brain

Central nervous system myelination increases action potential conduction velocity, however, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials, and facilitate information processing within cortical and associative circuits. Here, we show that mature myelin remains plastic in the adult mouse brain and can undergo subtle structural modifications to influence action potential arrival times. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and tunes conduction velocity to increase the synchronicity of action potential transit.

neuroscience↗