Local axonal morphology guides the topography of interneuron myelination in mouse and human neocortex

Stedehouder, Jeffrey; Brizee, Demi; Slotman, Johan A.; Pascual-Garcia, Maria; Leyrer, Megan L.; Bouwen, Bibi L. J.; Dirven, Clemens; Gao, Zhenyu; Berson, David M.; Houtsmuller, Adriaan B.; Kushner, Steven A.

doi:10.7554/elife.48615

Cited by 69 publications

(106 citation statements)

References 64 publications

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“…Hence these results point to a critical role of FSI myelination in guiding proximal axon morphology. Conversely, a recent report shows that FSI morphology is important to guide myelination 37 . The authors show that the enlargement of FSI size by genetic manipulations increases axonal myelination, while a decreased cell size leads to a reduced myelination 37 .…”

Section: Discussionmentioning

confidence: 97%

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

et al. 2020

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Myelination of projection neurons by oligodendrocytes is key to optimize action potential conduction over long distances. However, a large fraction of myelin enwraps the axons of parvalbumin-positive fast-spiking interneurons (FSI), exclusively involved in local cortical circuits. Whether FSI myelination contributes to the fine‐tuning of intracortical networks is unknown. Here we demonstrate that FSI myelination is required for the establishment and maintenance of the powerful FSI-mediated feedforward inhibition of cortical sensory circuits. The disruption of GABAergic synaptic signaling of oligodendrocyte precursor cells prior to myelination onset resulted in severe FSI myelination defects characterized by longer internodes and nodes, aberrant myelination of branch points and proximal axon malformation. Consequently, high-frequency FSI discharges as well as FSI-dependent postsynaptic latencies and strengths of excitatory neurons were reduced. These dysfunctions generated a strong excitation-inhibition imbalance that correlated with whisker-dependent texture discrimination impairments. FSI myelination is therefore critical for the function of mature cortical inhibitory circuits.

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Section: Discussionmentioning

confidence: 97%

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

et al. 2020

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“…The variety of Kv channel genes expressed by PV neurons is highly conserved between mouse and human neocortex (Okaty et al, 2009;Enwright et al, 2018;Krienen et al, 2019)(http://interneuron.mccarrolllab.org/). These and other similarities in voltage-gated channel gene expression suggest that PV neurons from human neocortex display FS properties, as verified experimentally (Wang et al, 2016;Stedehouder et al, 2017;Szegedi et al, 2017;Stedehouder et al, 2019;Szegedi et al, 2020). Hence, Kcns3 deficiency may produce qualitatively similar electrophysiological changes in PV neurons whether from mouse or human cortex.…”

Section: Implications For Cortical Circuit Dysfunction In Schizophreniamentioning

confidence: 52%

Kcns3Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia

Miyamae

Hashimoto

Abraham

et al. 2020

Preprint

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The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. We therefore assessed the role of Kv9.3 subunits in PV neuron function by combining gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient miceKcns3 mRNA levels were ~50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation, possibly due to a smaller afterhyperpolarization. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing, and smaller afterhyperpolarization. Moreover, Kcns3 deficiency impaired the recruitment of PVBCs by stimuli mimicking synaptic input during cortical UP states, which elicited bursts of spikes at gamma frequency. Our data suggest that Kv9.3 subunits are critical for PVBC physiology, and that KCNS3 deficiency in schizophrenia may impair the substrate of gamma oscillations.Significance statementIn the neocortex, Kcns3, the gene encoding voltage-dependent potassium (Kv) channel subunits Kv9.3, is selectively expressed by parvalbumin-positive (PV) neurons. Moreover, KCNS3 expression is decreased in PV neurons in schizophrenia. Kv 9.3 subunits are believed to amplify the current mediated by Kv2.1 subunits, however Kv9.3 function has not been investigated in PV cells.Here, simulations in a computational model and electrophysiological experiments with Kcns3-deficient mice revealed that Kcns3 deficiency disrupts repetitive firing in cortical PV neurons, possibly enhancing Na+ channel inactivation, and particularly with stimuli eliciting firing at gamma frequency band (30-80Hz). Our results suggest that Kv9.3 subunits are essential for PV neuron electrophysiology and that KCNS3 deficiency likely contributes to PV neuron dysfunction and gamma oscillation impairments in schizophrenia.

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“…Conversely, most cortical interneurons have short but elaborate axonal processes that reside in the same cortical area (34). A large fraction of cortical interneuron axons are myelinated in rodents and humans, the majority of which belong to the PV+ basket cells, the most abundant cortical interneuron subtype (19)(20)(21)(22)35). In mouse, approximately 65% of each PV+ axon is covered by myelin compared to approximately 25% for SST+ and 10% for vasoactive intestinal polypeptide expressing interneurons suggesting that these different myelination patterns reflect nuances in the importance of myelination for each neuronal subtype (19).…”

Section: Discussionmentioning

confidence: 99%

Demyelination induces selective vulnerability of inhibitory networks in multiple sclerosis

Zoupi¹,

Booker²,

Eigel

et al. 2020

Preprint

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In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination proved that this selective neurodegeneration is secondary to demyelination providing the first temporal evidence of demyelination-induced neurodegeneration and a new preclinical model for the study of neuroprotective treatments.

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Local axonal morphology guides the topography of interneuron myelination in mouse and human neocortex

Cited by 69 publications

References 64 publications

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

Kcns3Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia

Demyelination induces selective vulnerability of inhibitory networks in multiple sclerosis

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