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Cited by 149Stress Responses and CortisolNeuroscience and Neuropharmacology ResearchNeuropeptides and Animal Physiology

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GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response

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Gunn, Benjamin G., Cunningham, Linda, Mitchell, Scott G., Swinny, Jerome D., Lambert, Jeremy J., Belelli, Delia·2015·Frontiers in Neuroendocrinology
DOI 10.1016/j.yfrne.2014.06.001PMC PMC4349499
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Abstract

Regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioural changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.

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Fig. 1 Synaptic and extra-synaptic GABAAR isoforms, neurosteroid synthesising enzymes and 5α3α-reduced pregnane steroids in the stress neurocircuitry. Diagrammatic representation of a sagittal section of a rodent brain depicting the expression profile of GABAA receptor isoforms, the neurosteroid synthesising enzymes 5α-reductase (5α-R) and 3α-HSD and the distribution of GABAAR-modulating 5α3α-reduced pregnane steroids (e.g. 5α3α-THPROG), within the stress neurocircuitry. The reported expression of GABAAR subtypes is derived from both immunohistochemical and electrophysiological studies as referenced below. Note that GABAAR isoforms responsible for mediating phasic and tonic inhibition are expressed in a neurone-specific manner throughout the stress neurocircuitry. Note that for simplicity GABAAR isoforms expressed in various regions of the amygdala are not displayed but a discussion can be found in (Marowsky et al., 2012; Herman et al., 2013). Similarly, 5α-R, 3-HSD and 5α3α-reduced pregnane steroids have been detected across the stress axis albeit their levels exhibit distinct region-selective expression profile. References for the region-selective expression for the above enzymes are the following: prefrontal cortex, (PFC; Grobin et al., 2003; Castelli et al., 2013; Mitev et al., 2003); hippocampus, (Saalmann et al., 2007; Agis-Balboa et al., 2006; Castelli et al., 2013) and amygdaloid nuclei (Saalmann et al., 2007; Castelli et al., 2013; Do Rego et al., 2009; Mitev et al., 2003). The nucleus of the solitary tract (NTS) and the locus coreleus (LC), which directly innervate the PVN both exhibited immuno-reactivity for the 5α3α-reduced pregnane steroids (Saalmann et al., 2007), while 5α-R has been reported in LC and in the dorsal raphe (DR) nucleus (Castelli et al., 2013). Both the lateral septum (LS) and the bed nucleus of the solitary tract (BST) show immuno-reactivity for 5α3α-reduced pregnane steroid, while the relative expression of 5α-R and 3α-HSD remains to be determined. 5α-R expression has been shown in the nucleus accumbens shell, and to lesser extent in the core, while the presence of 3α-HSD and 5α3α-reduced neurosteroids remains to be determined. The hypothalamus displays an abundant expression of 5α-R and 3α-HSD abundantly (Li et al., 1997; Gao et al., 2002; Eechaute et al., 1999), although the expression in specific sub-regions requires further analysis. Within the PVN specifically, only the expression of 5α-R has been confirmed (Castelli et al., 2013), while dense 5α3α-reduced pregnane steroid immunoreactivity has been found in the periventricular zone (Saalmann et al., 2007). See also Section 2.1 and Fig. 2 for additional details. The bottom right panel depicts enzymatic steps that mediate 5α3α-THPROG synthesis from progesterone and describes the inhibitors of the individual enzymatic steps. (See above-mentioned references for further information.)
Fig. 1 Synaptic and extra-synaptic GABAAR isoforms, neurosteroid synthesising enzymes and 5α3α-reduced pregnane steroids in the stress neurocircuitry. Diagrammatic representation of a sagittal section of a rodent brain depicting the expression profile of GABAA receptor isoforms, the neurosteroid synthesising enzymes 5α-reductase (5α-R) and 3α-HSD and the distribution of GABAAR-modulating 5α3α-reduced pregnane steroids (e.g. 5α3α-THPROG), within the stress neurocircuitry. The reported expression of GABAAR subtypes is derived from both immunohistochemical and electrophysiological studies as referenced below. Note that GABAAR isoforms responsible for mediating phasic and tonic inhibition are expressed in a neurone-specific manner throughout the stress neurocircuitry. Note that for simplicity GABAAR isoforms expressed in various regions of the amygdala are not displayed but a discussion can be found in (Marowsky et al., 2012; Herman et al., 2013). Similarly, 5α-R, 3-HSD and 5α3α-reduced pregnane steroids have been detected across the stress axis albeit their levels exhibit distinct region-selective expression profile. References for the region-selective expression for the above enzymes are the following: prefrontal cortex, (PFC; Grobin et al., 2003; Castelli et al., 2013; Mitev et al., 2003); hippocampus, (Saalmann et al., 2007; Agis-Balboa et al., 2006; Castelli et al., 2013) and amygdaloid nuclei (Saalmann et al., 2007; Castelli et al., 2013; Do Rego et al., 2009; Mitev et al., 2003). The nucleus of the solitary tract (NTS) and the locus coreleus (LC), which directly innervate the PVN both exhibited immuno-reactivity for the 5α3α-reduced pregnane steroids (Saalmann et al., 2007), while 5α-R has been reported in LC and in the dorsal raphe (DR) nucleus (Castelli et al., 2013). Both the lateral septum (LS) and the bed nucleus of the solitary tract (BST) show immuno-reactivity for 5α3α-reduced pregnane steroid, while the relative expression of 5α-R and 3α-HSD remains to be determined. 5α-R expression has been shown in the nucleus accumbens shell, and to lesser extent in the core, while the presence of 3α-HSD and 5α3α-reduced neurosteroids remains to be determined. The hypothalamus displays an abundant expression of 5α-R and 3α-HSD abundantly (Li et al., 1997; Gao et al., 2002; Eechaute et al., 1999), although the expression in specific sub-regions requires further analysis. Within the PVN specifically, only the expression of 5α-R has been confirmed (Castelli et al., 2013), while dense 5α3α-reduced pregnane steroid immunoreactivity has been found in the periventricular zone (Saalmann et al., 2007). See also Section 2.1 and Fig. 2 for additional details. The bottom right panel depicts enzymatic steps that mediate 5α3α-THPROG synthesis from progesterone and describes the inhibitors of the individual enzymatic steps. (See above-mentioned references for further information.)CC BY · PubMed Central
Fig. 2 The stress neurocircuitry. A schematic representation of a sagittal section of a rodent brain, illustrating the neurocircuitry involved in the stress-induced regulation of HPA axis activity, with a particular emphasis on the nature of direct excitatory (blue) and inhibitory (red) projections to the PVN and the complex polysynaptic inputs mediating limbic and forebrain influences upon the stress response. The PVN receives direct noradrenergic, adrenergic and peptidergic innervation from the nucleus of solitary tract (NTS), as well as direct PVN-projecting noradrenergic and serotonergic afferents originating in the locus coreleus (LC) and dorsal raphe nucleus (DR). Projection from the bed nucleus of the stria terminalis (BST) are the main, non-hypothalamic forebrain inputs to the PVN, exerting both excitatory and inhibitory influences upon HPA axis activity. Thus, glutamatergic and CRFergic projections to the PVN originating in the anterior BST (aBST) stimulate HPA axis activity, whilst inhibitory GABAergic inputs originate in the posterior BST (pBST). Importantly the BST acts as primary relay site for limbic and forebrain inputs that have a substantial influence upon HPA axis activity (A, B and C). Direct inhibitory inputs to the PVN originate in a number of hypothalamic nuclei (D), including the medial preoptic area (mPOA), ventrolateral dorsal hypothalamus (vlDMH) and the peri-PVN (pPVN), while PVN-projecting afferents from the dorsomedial dorsal hypothalamus (dmDMH) provide intra-hypothalamic excitation to the HPA axis. Limbic and forebrain regions impart a significant influence upon the activity of the HPA axis, via indirect polysynaptic inputs to the PVN. The medial prefrontal cortex (mPFC) influences HPA axis activity in a subregion-specific manner (A). Thus, the prelimbic (PL) mPFC inhibits response to psychogenic stressors primarily via glutamatergic projections to inhibitory GABAergic relay nuclei (e.g. aBST, pPVN). In contrast, the infralimbic (IL) mPFC has been postulated to activate HPA axis activity possibly via projections to the NTS and/or CeA. Hippocampal stress output is mediated by glutamtergic projections from the ventral subiculum (vSUB) to primarily GABAergic relay nuclei (e.g. mPOA, pPVN, pBST and DMH), thereby inhibiting HPA axis activity (B). The amygdala exerts a primarily excitatory influence upon HPA axis activity, although this appears to occur in a subregion and stressor specific manner. Inhibitory, GABAergic projections from the central (CeA) and medial (MeA) amygdala disinhibit GABAergic relay nuclei (e.g. mPOA, aBST and DMH) to regulate responses to physical and psychogenic stressors respectively. Glutamatergic projections originating in the basolateral (BLA) amygdala innervate the CeA, MeA and BST, primarily increasing HPA axis activity in general in response to psychogenic stressors (C). The lateral septum (LS) also modulates HPA axis activity (pathways not shown) via polysynaptic inputs to the PVN. Furthermore, the nucleus accumbens (nAcc), which is primary component of the reward circuitry, may also be important in the regulation of HPA axis activity, providing a structural connection between the stress and reward circuitry. Although the influence the nAcc imparts upon HPA axis activity remains to be elucidated, projections from the nAcc core and shell to PVN-projecting brain regions such as the BST, lateral POA and lateral hypothalamus (LH) provide an anatomical basis for potential physiological effects upon the HPA axis (not shown). Further evidence for an interaction between the reward and stress systems is suggested by the observation that the receptors responsible for mediating the effects of glucocorticoids and CRF are expressed within the nAcc.
Fig. 2 The stress neurocircuitry. A schematic representation of a sagittal section of a rodent brain, illustrating the neurocircuitry involved in the stress-induced regulation of HPA axis activity, with a particular emphasis on the nature of direct excitatory (blue) and inhibitory (red) projections to the PVN and the complex polysynaptic inputs mediating limbic and forebrain influences upon the stress response. The PVN receives direct noradrenergic, adrenergic and peptidergic innervation from the nucleus of solitary tract (NTS), as well as direct PVN-projecting noradrenergic and serotonergic afferents originating in the locus coreleus (LC) and dorsal raphe nucleus (DR). Projection from the bed nucleus of the stria terminalis (BST) are the main, non-hypothalamic forebrain inputs to the PVN, exerting both excitatory and inhibitory influences upon HPA axis activity. Thus, glutamatergic and CRFergic projections to the PVN originating in the anterior BST (aBST) stimulate HPA axis activity, whilst inhibitory GABAergic inputs originate in the posterior BST (pBST). Importantly the BST acts as primary relay site for limbic and forebrain inputs that have a substantial influence upon HPA axis activity (A, B and C). Direct inhibitory inputs to the PVN originate in a number of hypothalamic nuclei (D), including the medial preoptic area (mPOA), ventrolateral dorsal hypothalamus (vlDMH) and the peri-PVN (pPVN), while PVN-projecting afferents from the dorsomedial dorsal hypothalamus (dmDMH) provide intra-hypothalamic excitation to the HPA axis. Limbic and forebrain regions impart a significant influence upon the activity of the HPA axis, via indirect polysynaptic inputs to the PVN. The medial prefrontal cortex (mPFC) influences HPA axis activity in a subregion-specific manner (A). Thus, the prelimbic (PL) mPFC inhibits response to psychogenic stressors primarily via glutamatergic projections to inhibitory GABAergic relay nuclei (e.g. aBST, pPVN). In contrast, the infralimbic (IL) mPFC has been postulated to activate HPA axis activity possibly via projections to the NTS and/or CeA. Hippocampal stress output is mediated by glutamtergic projections from the ventral subiculum (vSUB) to primarily GABAergic relay nuclei (e.g. mPOA, pPVN, pBST and DMH), thereby inhibiting HPA axis activity (B). The amygdala exerts a primarily excitatory influence upon HPA axis activity, although this appears to occur in a subregion and stressor specific manner. Inhibitory, GABAergic projections from the central (CeA) and medial (MeA) amygdala disinhibit GABAergic relay nuclei (e.g. mPOA, aBST and DMH) to regulate responses to physical and psychogenic stressors respectively. Glutamatergic projections originating in the basolateral (BLA) amygdala innervate the CeA, MeA and BST, primarily increasing HPA axis activity in general in response to psychogenic stressors (C). The lateral septum (LS) also modulates HPA axis activity (pathways not shown) via polysynaptic inputs to the PVN. Furthermore, the nucleus accumbens (nAcc), which is primary component of the reward circuitry, may also be important in the regulation of HPA axis activity, providing a structural connection between the stress and reward circuitry. Although the influence the nAcc imparts upon HPA axis activity remains to be elucidated, projections from the nAcc core and shell to PVN-projecting brain regions such as the BST, lateral POA and lateral hypothalamus (LH) provide an anatomical basis for potential physiological effects upon the HPA axis (not shown). Further evidence for an interaction between the reward and stress systems is suggested by the observation that the receptors responsible for mediating the effects of glucocorticoids and CRF are expressed within the nAcc.CC BY · PubMed Central
Fig. 3 Adverse early-life experience induces significant functional and morphological plasticity in the neonatal mouse PVN. A. Immunohistochemical analysis illustrating the expression of CRF (pink) and the astrocytic cytoskeleton protein GFAP (green) in coronal sections of the neonatal hypothalamic PVN under control breeding conditions (left) and following exposure to ELS (right). Note that following ELS the expression of CRF in medial parvocellular neurones (mpd) increases while GFAP immunoreactive arbours become thinner. B. Immunuhistochemical analysis illustrating at high magnification the excitatory glutamatergic inputs measured by vGLUT2 expression (blue) apposing neonatal CRF-releasing neurones of mice bred under normal condition (left) or exposed to ELS (right). Note the significant increase in the number of excitatory glutamatergic (blue) inputs apposing neonatal CRF-releasing neurones exposed to ELS. C. Diagrammatic representation of the changes occurring at the glutamatergic synapses of CRF-releasing mpd neurones as a consequence of abnormal maternal care. Functional and molecular findings indicate an increase in phasic glutamatergic currents and an elevated excitatory tonic conductance in ELS compared to control neurones. The latter effect in mice exposed to ELS is mediated, at least in part, by the reduced clearance of glutamate from the synapse caused by a reduction in the expression of astrocytic glutamate transporters. In ELS-exposed mice, the increased glutamatergic drive associates with a loss of the inhibitory actions of the naturally occurring progesterone metabolite 5α3α THPROG upon the neuronal discharge of CRF-releasing mpd neurones. In this regard, compare cell-attached recordings before and after 5α3α THPROG shown to the right and left side of the diagrammatic synapses for Control and ELS neurones respectively. Note that the changes described above for ELS mice are shared by a genetic mouse model of postnatal depression, the δ “knock-out” mice, which also experience abnormal maternal care (Gunn et al., 2013).
Fig. 3 Adverse early-life experience induces significant functional and morphological plasticity in the neonatal mouse PVN. A. Immunohistochemical analysis illustrating the expression of CRF (pink) and the astrocytic cytoskeleton protein GFAP (green) in coronal sections of the neonatal hypothalamic PVN under control breeding conditions (left) and following exposure to ELS (right). Note that following ELS the expression of CRF in medial parvocellular neurones (mpd) increases while GFAP immunoreactive arbours become thinner. B. Immunuhistochemical analysis illustrating at high magnification the excitatory glutamatergic inputs measured by vGLUT2 expression (blue) apposing neonatal CRF-releasing neurones of mice bred under normal condition (left) or exposed to ELS (right). Note the significant increase in the number of excitatory glutamatergic (blue) inputs apposing neonatal CRF-releasing neurones exposed to ELS. C. Diagrammatic representation of the changes occurring at the glutamatergic synapses of CRF-releasing mpd neurones as a consequence of abnormal maternal care. Functional and molecular findings indicate an increase in phasic glutamatergic currents and an elevated excitatory tonic conductance in ELS compared to control neurones. The latter effect in mice exposed to ELS is mediated, at least in part, by the reduced clearance of glutamate from the synapse caused by a reduction in the expression of astrocytic glutamate transporters. In ELS-exposed mice, the increased glutamatergic drive associates with a loss of the inhibitory actions of the naturally occurring progesterone metabolite 5α3α THPROG upon the neuronal discharge of CRF-releasing mpd neurones. In this regard, compare cell-attached recordings before and after 5α3α THPROG shown to the right and left side of the diagrammatic synapses for Control and ELS neurones respectively. Note that the changes described above for ELS mice are shared by a genetic mouse model of postnatal depression, the δ “knock-out” mice, which also experience abnormal maternal care (Gunn et al., 2013).CC BY · PubMed Central
Fig. 4 The brain levels of 5α3α-THPROG are developmentally regulated. Diagrammatic illustration of rat cortical levels (arbitrary units) of 5α3α-THPROG across various developmental stages. During embryonic development the levels of 5α3α-THPROG decrease considerably at E20 before increasing prior to parturition. The relatively high levels of 5α3α-THPROG at birth (P0), decline gradually over the first postnatal week until P10, when they rise again to levels comparable to those observed at birth. This transient increase lasts until P15, when the levels of 5α3α-THPROG decline back to basal values. Interestingly, the early postnatal period, which is associated with generally elevated levels of 5α3α-THPROG coincides with the so-called stress hypo-responsive period (SHRP, P2-P14). Furthermore, the secondary transient peak (at P10) in cortical neurosteroid levels coincides with significant developmental changes associated with GABAAR-mediated inhibition within the CNS. As detailed, during this developmental stage, at P9–P10 the actions of GABA switch from being depolarising to hyperpolarising as a consequence of the increased expression of the potassium-chloride co-transporter, KCC2, thus causing a subsequent reduction in intracellular Cl-concentration. Shortly after this change, the further development of the rodent visual cortex begins at ∼P14 following eye opening. This early period of significant neuronal and network maturation is additionally accompanied by significant developmental changes in the GABAAR subunit expression, typified by a switch from the embryonic α2/3 to adult α1 subunits, which takes places throughout the second and third postnatal weeks. Although, in adulthood the basal levels of 5α3α-THPROG are typically lower than during early postnatal development, they are dynamically elevated in response to specific physiological conditions, including acute stressor exposure and during pregnancy.
Fig. 4 The brain levels of 5α3α-THPROG are developmentally regulated. Diagrammatic illustration of rat cortical levels (arbitrary units) of 5α3α-THPROG across various developmental stages. During embryonic development the levels of 5α3α-THPROG decrease considerably at E20 before increasing prior to parturition. The relatively high levels of 5α3α-THPROG at birth (P0), decline gradually over the first postnatal week until P10, when they rise again to levels comparable to those observed at birth. This transient increase lasts until P15, when the levels of 5α3α-THPROG decline back to basal values. Interestingly, the early postnatal period, which is associated with generally elevated levels of 5α3α-THPROG coincides with the so-called stress hypo-responsive period (SHRP, P2-P14). Furthermore, the secondary transient peak (at P10) in cortical neurosteroid levels coincides with significant developmental changes associated with GABAAR-mediated inhibition within the CNS. As detailed, during this developmental stage, at P9–P10 the actions of GABA switch from being depolarising to hyperpolarising as a consequence of the increased expression of the potassium-chloride co-transporter, KCC2, thus causing a subsequent reduction in intracellular Cl-concentration. Shortly after this change, the further development of the rodent visual cortex begins at ∼P14 following eye opening. This early period of significant neuronal and network maturation is additionally accompanied by significant developmental changes in the GABAAR subunit expression, typified by a switch from the embryonic α2/3 to adult α1 subunits, which takes places throughout the second and third postnatal weeks. Although, in adulthood the basal levels of 5α3α-THPROG are typically lower than during early postnatal development, they are dynamically elevated in response to specific physiological conditions, including acute stressor exposure and during pregnancy.CC BY · PubMed Central

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Authors
Gunn, B. G., Cunningham, L., Mitchell, S. G., Swinny, J. D., Lambert, J. J., & Belelli, D.
Affiliations
  • University of Dundee (GB)
  • University of Portsmouth (GB)
Corresponding author
Belelli, Delia
ORCID
Venue
Frontiers in Neuroendocrinology
Publisher
Elsevier BV
Published
2015-01
Volume
36
Pages
28-48
ISSN
0091-3022 (ISSN-L)
DOI
10.1016/j.yfrne.2014.06.001
PMC
PMC4349499
OpenAlex
W2113668852
Cited by
149
References
317
Citations by year
2026: 2 · 2025: 13 · 2024: 8 · 2023: 10 · 2022: 18 · 2021: 8 · 2020: 16 · 2019: 20 · 2018: 14 · 2017: 16 · 2016: 7 · 2015: 11
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroendocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
Funders
  • Wellbeing of Women (RG1265)
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
GABAA receptor, neurosteroids, hypothalamic-pituitary-adrenal axis, stress response, childhood adversity, maternal care, chronic stress, stress-protective effect, mood disorders, intergenerational transmission
MeSH terms
Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Receptors, GABA-A, Stress, Psychological, Neurotransmitter Agents

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