Endogenous neurosteroids influence synaptic GABAA receptors during post-natal development

D. Belelli, A. R. Brown, S. J. Mitchell, B. G. Gunn, M. B. Herd, G. D. Phillips, Mohsen Seifi, Jerome D. Swinny, J. J. Lambert (Lead / Corresponding author)

    Research output: Contribution to journalReview article

    5 Citations (Scopus)
    100 Downloads (Pure)

    Abstract

    GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABA A receptors (GABA ARs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABA ARs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABA AR are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principal- and inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABA AR function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABA AR subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios. Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABA AR-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABA AR interaction early in life may contribute to psychiatric conditions later in life.

    Original languageEnglish
    Article numbere12537
    Pages (from-to)11-15
    Number of pages5
    JournalJournal of Neuroendocrinology
    Volume30
    Issue number2
    Early online date14 Sep 2017
    DOIs
    Publication statusPublished - 18 Feb 2018

    Fingerprint

    Neurotransmitter Receptor
    GABA-A Receptors
    Neurotransmitter Agents
    Synaptic Transmission
    gamma-Aminobutyric Acid
    Neurons
    Pregnanolone
    Inhibitory Postsynaptic Potentials
    Neuronal Plasticity
    Brain
    Thalamus
    Nervous System
    Psychiatry

    Keywords

    • GABA receptor
    • cortex
    • neurosteroid
    • synaptic inhibition
    • thalamus

    Cite this

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    title = "Endogenous neurosteroids influence synaptic GABAA receptors during post-natal development",
    abstract = "GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABA A receptors (GABA ARs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABA ARs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABA AR are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principal- and inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABA AR function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABA AR subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios. Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABA AR-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABA AR interaction early in life may contribute to psychiatric conditions later in life.",
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    Endogenous neurosteroids influence synaptic GABAA receptors during post-natal development. / Belelli, D.; Brown, A. R.; Mitchell, S. J.; Gunn, B. G.; Herd, M. B.; Phillips, G. D.; Seifi, Mohsen; Swinny, Jerome D.; Lambert, J. J. (Lead / Corresponding author).

    In: Journal of Neuroendocrinology, Vol. 30, No. 2, e12537, 18.02.2018, p. 11-15.

    Research output: Contribution to journalReview article

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    T1 - Endogenous neurosteroids influence synaptic GABAA receptors during post-natal development

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    AU - Brown, A. R.

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    AU - Gunn, B. G.

    AU - Herd, M. B.

    AU - Phillips, G. D.

    AU - Seifi, Mohsen

    AU - Swinny, Jerome D.

    AU - Lambert, J. J.

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    N2 - GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABA A receptors (GABA ARs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABA ARs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABA AR are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principal- and inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABA AR function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABA AR subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios. Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABA AR-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABA AR interaction early in life may contribute to psychiatric conditions later in life.

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