Endogenous neurosteroids influence synaptic GABA_A receptors during postnatal 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 A Rs), 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 A Rs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABA A R are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principaland inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABA A R 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 A R 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 A R-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 A R interaction early in life may contribute to psychiatric conditions later in life. K E Y W O R D Scortex, GABA A receptor, neurosteroid, synaptic inhibition, thalamus

Signatures of sex: Sex differences in gene expression in the vertebrate brain

“…Steroidogenesis also occurs in the placenta, and in both sexes, the adrenal cortex and brain. Many locally derived "neurosteroids" influence brain development and function (Belelli et al, 2018;Do Rego et al, 2009;London, 2016). Classic experiments have demonstrated that manipulation of hormone levels can profoundly alter sex-typical reproductive and BOX 1 TOOLS FOR STUDYING GENE REGULATORY MECHANISMS IN SPECIFIC CELL TYPES OF THE MOUSE BRAIN Several molecular genetic tools have been developed for studying gene regulation in the mammalian brain.…”

Progesterone and anxiety during the oestrus cycle in rats genetically selected for high and low active avoidance

“…It was named a neurosteroid in 1981 by Baulieu's team, who discovered that the brain "acting like a peripheral gland" expresses the enzymatic machinery required to synthesise allopregnanolone de novo starting from pregnenolone, the precursor of all neurosteroids (Corpéchot et al 1981). Allopregnanolone's anti-convulsant, anxiolytic and anti-depressant pharmacological effects after its administration in animals and humans were soon recognised to be mediated by a mechanism of action that includes the fast allosteric modulation of the action of GABA at GABA A receptors (Majewska et al 1986;Belelli et al 2018). The neurophysiological role of allopregnanolone in permitting the finetuning and regulation of the strength of GABA A receptors to agonists, positive allosteric modulators, and GABAmimetic agents, was also unveiled (Pinna et al 2000).…”

Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease

“…Importantly, the affinity and relative potency of 3α-hydroxy, 5α-reduced for the GABA A receptor is highly dependent on the subunit composition of the receptor itself. The GABA A receptor is a pentamer that is typically composed of two α subunits (α1–6), two β subunits (β1–4), and one additional subunit that is either a γ (γ1–3), δ, ε, π, or θ, or ρ (ρ1–3; Sieghart, 2006 ; Reddy and Jian, 2010 ; Belelli et al, 2018 ). A low-affinity human β3 homopentamer of the GABA A has been identified as well (Miller and Aricescu, 2014 ), though this conformation of the receptor does not appear to be neurosteroid-sensitive, probably due to the lack of α subunits (Nik et al, 2017 ).…”