Axonal sodium channel NaV1.2 drives granule cell dendritic GABA release and rapid odor discrimination

Nunes, Daniel; Kuner, Thomas

doi:10.1371/journal.pbio.2003816

Cited by 27 publications

(33 citation statements)

References 68 publications

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“…However, both male and female Scn2a gtKO/gtKO mice showed no significant difference from WT in olfactory preference for cinnamon over water. Our olfactory results are similar to a Nav1.2 shRNA knockdown mouse model which also had an increase in time for the mice to discriminate the odorants [41].…”

Section: Discussionsupporting

confidence: 79%

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

Eaton

Zhang

et al. 2020

Preprint

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Recent large-scale genomic studies have revealed SCN2A as one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability. SCN2A encodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) of Scn2a is perinatal lethal, whereas heterozygous knockout of Scn2a results in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction of Scn2a expression, we characterized a Scn2a deficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-function SCN2A disorders. This model produces viable homozygous mice (Scn2a gtKO/gtKO ) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. Although Scn2a gtKO/gtKO adult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novel Scn2a gene trap knockout mouse thus provides a unique model to study pathophysiology associated with Scn2a deficiency.

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Section: Discussionsupporting

confidence: 79%

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

Eaton

Zhang

et al. 2020

Preprint

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“…One possible mechanism to explain this result is that learning to discriminate the enantiomers involves changes in the interactions between M/T and local inhibitory neurons in the ipsi-OB which enhance the differences in the representations of the two previously indistinguishable odorants. Evidence of the involvement of local inhibitory neurons in learning to discriminate highly similar odorants has been reported [114][115][116][117] . These changes in local interneurons might only occur on the ipsi-side (perhaps because they might need high activation).…”

Section: Ipsilateral and Contralateral Odorant Discrimination And Genmentioning

confidence: 99%

Bilateral and unilateral odor processing and odor perception

2020

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Imagine smelling a novel perfume with only one nostril and then smelling it again with the other nostril. Clearly, you can tell that it is the same perfume both times. This simple experiment demonstrates that odor information is shared across both hemispheres to enable perceptual unity. In many sensory systems, perceptual unity is believed to be mediated by inter-hemispheric connections between iso-functional cortical regions. However, in the olfactory system, the underlying neural mechanisms that enable this coordination are unclear because the two olfactory cortices are not topographically organized and do not seem to have homotypic inter-hemispheric mapping. This review presents recent advances in determining which aspects of odor information are processed unilaterally or bilaterally, and how odor information is shared across the two hemispheres. We argue that understanding the mechanisms of inter-hemispheric coordination can provide valuable insights that are hard to achieve when focusing on one hemisphere alone. I n the early 1940s, patients suffering from severe untreatable epileptic seizures underwent a pioneering operation in which their corpus callosum was severed. While this mitigated the epilepsy syndromes, it generated strange phenomena: each hemisphere seemed to have its own separate perception, concepts, and even actions. When such split-brain patients were shown an image of an object in their left visual field, they could not vocally name what they had seen. This is because information about the image seen in the left visual field is sent only to the right side of the brain, while the speech-control center is usually on the left side of the brain. Nonetheless, patients could pick up the correct object with their left hand because it is controlled by the right hemisphere 1. Some of the surgery-induced deficits improved over time, but they illustrate one important principle: the fibers that interconnect the hemispheres are responsible for transferring information from one side to the other. These connecting fibers may be required to achieve perceptual unity, at least in some sensory modalities. But how is perceptual unity achieved? There are several possible ways to achieve perceptual unity in the healthy brain. One way is to ensure that sensory information is transmitted to both hemispheres directly from the sensory organs. This is how auditory information is unified across hemispheres: information from both ears converges to the left and the right Superior Olivary

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“…Discussion). The afterhyperpolarization (AHP) following single MC APs elicited by somatic current injection was found to mainly reflect recurrent inhibition in brain slices from adult mouse(Nunes & Kuner 2018), while in juvenile rat inhibitory synaptic contributions to the AHP were observed to be less substantial but still detectable (on the order of 20-30% relative to the K + channel-mediated component, Dumenieu et al 2015). We used this paradigm to test whether NMDAR blockade alone could interfere with recurrent inhibition(Fig.…”

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confidence: 99%

Presynaptic NMDA receptors cooperate with local action potentials to implement activity-dependent GABA release from the reciprocal olfactory bulb granule cell spine

Lage-Rupprecht

Zhou

Bianchini

et al. 2018

Preprint

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AbstractIn the rodent olfactory bulb the smooth dendrites of the principal glutamatergic mitral cells (MCs) form reciprocal dendrodendritic synapses with large spines on GABAergic granule cells (GC), where unitary release of glutamate can trigger postsynaptic local activation of voltage-gated Na+-channels (Navs), i.e. a spine spike. Can such single MC inputs evoke reciprocal release? We find that unitary-like activation via two-photon uncaging of glutamate causes GC spines to release GABA both synchronously and asynchronously onto MC dendrites. This release indeed requires activation of Navs and high-voltage-activated Ca2+-channels (HVACCs), but also of NMDA receptors (NMDAR). Simulations show temporally overlapping HVACC- and NMDAR-mediated Ca2+-currents during the spine spike, and ultrastructural data prove NMDAR presence within the GABAergic presynapse. The cooperative action of presynaptic NMDARs allows to implement synapse-specific, activity-dependent and non-topographical lateral inhibition and thus could provide an efficient solution to combinatorial percept synthesis in a sensory system with many receptor channels.

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Axonal sodium channel NaV1.2 drives granule cell dendritic GABA release and rapid odor discrimination

Cited by 27 publications

References 68 publications

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

Bilateral and unilateral odor processing and odor perception

Presynaptic NMDA receptors cooperate with local action potentials to implement activity-dependent GABA release from the reciprocal olfactory bulb granule cell spine

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