Current Biology

2020

DOI: 10.1016/j.cub.2020.03.071

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Nest Carbon Dioxide Masks GABA-Dependent Seizure Susceptibility in the Naked Mole-Rat

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Edward F. Meehan

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et al.

Abstract: Highlights d Eusocial African naked mole-rats raise colony-nest CO 2 to anticonvulsant levels d Naked mole-rats harbor an epilepsy-related variant in neuronal Clextruder KCC2 d GABA-acting antiseizure drug diazepam triggers seizures in naked mole-rats d Diazepam is rendered seizure-suppressing in nest-like levels of CO 2 in inhaled air

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Introduction2

Box 4 Kcc2 Mutations In Epilepsy1

Age Longevity and Brain Metabolism1

Ecophysiology and Environment1

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Cited by 25 publications

(27 citation statements)

References 70 publications

(113 reference statements)

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“…Importantly, the R952H variant is unable to support the two known ion transport-independent functions of KCC2the maintenance of dendritic spines [28] and the antiapoptotic effect on cortical projection neurons in embryonic neocortex [10]. Interestingly, histidine is also found at position 952 of the naked mole rat KCC2 [144], where it may have been favored by natural selection as one of the striking energy-metabolic adaptations [145] of this eusocial mammal.…”

Section: Box 4 Kcc2 Mutations In Epilepsymentioning

confidence: 99%

The Multifaceted Roles of KCC2 in Cortical Development

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et al. 2021

Trends in Neurosciences

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KCC2, best known as the neuron-specific chloride-extruder that sets the strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule that can regulate cytoskeletal dynamics via its C-terminal domain (CTD). We describe the molecular and cellular mechanisms involved in the multiple functions of KCC2 and its splice variants, ranging from developmental apoptosis and the control of early network events to the formation and plasticity of cortical dendritic spines. The versatility of KCC2 actions at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease, and aging. Thus, KCC2 has emerged as one of the most important molecules that shape the overall neuronal phenotype. KCC2 in the Fundamental Machinery Underlying Neuronal Development, Signaling, and StructureFast synaptic transmission relies on ion fluxes through ligand-gated ion channels. Although the default state of a cell is to have a high intracellular chloride concentration ([Cl − ] i ), mature neurons in the CNS have evolved a unique ability to maintain a low [Cl − ] i , which is needed for the generation of hyperpolarizing Cl − currents across GABA A and glycine receptors (GABA A Rs and GlyRs) [1]. This specialization comes at a high energy cost [2], and is brought about by upregulation of the neuron-specific K-Cl cotransporter KCC2 during neuronal maturation [1,3,4]. KCC2 belongs to the evolutionarily ancient family of SLC12 cation/chloride cotransporters (CCCs) (Box 1; for KCCs and NKCCs, see Glossary) that have their roots in a single gene in Archaea, from which numerous duplication events in both archaeans and eukaryotes have led to the divergence and neofunctionalization of the paralogous CCC subfamilies [5]. Possibly because of a primordial role in cellular volume regulation, CCCs have evolved to communicate with the actin cytoskeleton. Indeed, KCC2 has emerged as an important player in controlling actin dynamics during neuronal development and plasticity [6][7][8][9].The functional upregulation of KCC2-mediated K-Cl cotransport in hippocampal and neocortical neurons underlies the hyperpolarizing shift in GABAergic currents which takes place postnatally in rats and mice [3], but it has become clear that KCC2 is expressed at low but functionally significant levels pre-and perinatally. KCC2 acts in an ion transport-independent manner as an antiapoptotic factor in projection neurons in the prenatal mouse neocortex [10]; in the perinatal mouse and rat hippocampus transport-functional KCC2 decreases the depolarizing driving force of GABA A R-mediated currents (DF GABA ), thereby influencing spontaneous network events at their developmental onset [11].In this review we highlight the developmental paths from KCC2 protein expression to its multiple functions, and discuss the wide variety of post-translational mechanisms which control these phenomena. The versatility of KCC2 regulation at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease,...

“…Importantly, the R952H variant is unable to support the two known ion transport-independent functions of KCC2the maintenance of dendritic spines [28] and the antiapoptotic effect on cortical projection neurons in embryonic neocortex [10]. Interestingly, histidine is also found at position 952 of the naked mole rat KCC2 [144], where it may have been favored by natural selection as one of the striking energy-metabolic adaptations [145] of this eusocial mammal.…”

Section: Box 4 Kcc2 Mutations In Epilepsymentioning

confidence: 99%

The Multifaceted Roles of KCC2 in Cortical Development

¹

,

²

,

³

et al. 2021

Trends in Neurosciences

Self Cite

View full text Add to dashboard Cite

KCC2, best known as the neuron-specific chloride-extruder that sets the strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule that can regulate cytoskeletal dynamics via its C-terminal domain (CTD). We describe the molecular and cellular mechanisms involved in the multiple functions of KCC2 and its splice variants, ranging from developmental apoptosis and the control of early network events to the formation and plasticity of cortical dendritic spines. The versatility of KCC2 actions at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease, and aging. Thus, KCC2 has emerged as one of the most important molecules that shape the overall neuronal phenotype. KCC2 in the Fundamental Machinery Underlying Neuronal Development, Signaling, and StructureFast synaptic transmission relies on ion fluxes through ligand-gated ion channels. Although the default state of a cell is to have a high intracellular chloride concentration ([Cl − ] i ), mature neurons in the CNS have evolved a unique ability to maintain a low [Cl − ] i , which is needed for the generation of hyperpolarizing Cl − currents across GABA A and glycine receptors (GABA A Rs and GlyRs) [1]. This specialization comes at a high energy cost [2], and is brought about by upregulation of the neuron-specific K-Cl cotransporter KCC2 during neuronal maturation [1,3,4]. KCC2 belongs to the evolutionarily ancient family of SLC12 cation/chloride cotransporters (CCCs) (Box 1; for KCCs and NKCCs, see Glossary) that have their roots in a single gene in Archaea, from which numerous duplication events in both archaeans and eukaryotes have led to the divergence and neofunctionalization of the paralogous CCC subfamilies [5]. Possibly because of a primordial role in cellular volume regulation, CCCs have evolved to communicate with the actin cytoskeleton. Indeed, KCC2 has emerged as an important player in controlling actin dynamics during neuronal development and plasticity [6][7][8][9].The functional upregulation of KCC2-mediated K-Cl cotransport in hippocampal and neocortical neurons underlies the hyperpolarizing shift in GABAergic currents which takes place postnatally in rats and mice [3], but it has become clear that KCC2 is expressed at low but functionally significant levels pre-and perinatally. KCC2 acts in an ion transport-independent manner as an antiapoptotic factor in projection neurons in the prenatal mouse neocortex [10]; in the perinatal mouse and rat hippocampus transport-functional KCC2 decreases the depolarizing driving force of GABA A R-mediated currents (DF GABA ), thereby influencing spontaneous network events at their developmental onset [11].In this review we highlight the developmental paths from KCC2 protein expression to its multiple functions, and discuss the wide variety of post-translational mechanisms which control these phenomena. The versatility of KCC2 regulation at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease,...

“…These effects can be socially modulated in honey bees ( Li-Byarlay et al, 2014 ), potentially impacting aging and life history if it alters social roles. NMRs exhibit a point mutation in a neuronal potassium chloride cotransporter that lowers the energy costs of GABAergic signaling in low oxygen environments ( Zions et al, 2020 ), intriguingly suggesting an interaction between brain metabolism and environment. Interactions between abiotic conditions and aging related genes in termites ( Rau and Korb, 2021 ) suggest that metabolism-environment interactions could exist in many taxa.…”

Section: Age Longevity and Brain Metabolismmentioning

confidence: 99%

Eusociality and Senescence: Neuroprotection and Physiological Resilience to Aging in Insect and Mammalian Systems

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2021

Front. Cell Dev. Biol.

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Are eusociality and extraordinary aging polyphenisms evolutionarily coupled? The remarkable disparity in longevity between social insect queens and sterile workers—decades vs. months, respectively—has long been recognized. In mammals, the lifespan of eusocial naked mole rats is extremely long—roughly 10 times greater than that of mice. Is this robustness to senescence associated with social evolution and shared mechanisms of developmental timing, neuroprotection, antioxidant defenses, and neurophysiology? Focusing on brain senescence, we examine correlates and consequences of aging across two divergent eusocial clades and how they differ from solitary taxa. Chronological age and physiological indicators of neural deterioration, including DNA damage or cell death, appear to be decoupled in eusocial insects. In some species, brain cell death does not increase with worker age and DNA damage occurs at similar rates between queens and workers. In comparison, naked mole rats exhibit characteristics of neonatal mice such as protracted development that may offer protection from aging and environmental stressors. Antioxidant defenses appear to be regulated differently across taxa, suggesting independent adaptations to life history and environment. Eusocial insects and naked mole rats appear to have evolved different mechanisms that lead to similar senescence-resistant phenotypes. Careful selection of comparison taxa and further exploration of the role of metabolism in aging can reveal mechanisms that preserve brain functionality and physiological resilience in eusocial species.

“…When naked mole-rats huddle together in their nests, the animals at the bottom of the pile experience extreme hypoxia (e.g. Park et al, 2017;Zions et al, 2020) to the extent that they can lose consciousness and may take up to 15 min to recover when they are moved to a normoxic environment (S. Braude & S. Holtze, personal observations).…”

Section: Ecophysiology and Environmentmentioning

confidence: 99%

Surprisingly long survival of premature conclusions about naked mole‐rat biology

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et al. 2020

Biological Reviews

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Naked mole‐rats express many unusual traits for such a small rodent. Their morphology, social behaviour, physiology, and ageing have been well studied over the past half‐century. Many early findings and speculations about this subterranean species persist in the literature, although some have been repeatedly questioned or refuted. While the popularity of this species as a natural‐history curiosity, and oversimplified story‐telling in science journalism, might have fuelled the perpetuation of such misconceptions, an accurate understanding of their biology is especially important for this new biomedical model organism. We review 28 of these persistent myths about naked mole‐rat sensory abilities, ecophysiology, social behaviour, development and ageing, and where possible we explain how these misunderstandings came about.

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