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Istvan Mody - One of the best experts on this subject based on the ideXlab platform.

  • Behavioral Deficits in Juveniles Mediated by Maternal Stress Hormones in Mice
    Neural plasticity, 2015
    Co-Authors: Jamie Maguire, Istvan Mody
    Abstract:

    Maternal depression has been shown to negatively impact offspring development. Investigation into the impact of maternal depression and offspring behavior has relied on correlative studies in humans. Further investigation into the underlying mechanisms has been hindered by the lack of useful animal models. We previously characterized a mouse model which exhibits depression-like behaviors restricted to the postpartum period and abnormal/fragmented maternal care (GABRD−/− mice). Here we utilized this unique mouse model to investigate the mechanism(s) through which maternal depression-like behaviors adversely impact offspring development. Cross-fostering experiments reveal increased anxiety-like and depression-like behaviors in mice reared by GABRD−/− mothers. Wild type and GABRD−/− mice subjected to unpredictable stress during late pregnancy exhibit decreased pup survival and depression-like behavior in the postpartum period. Exogenous corticosterone treatment in wild type mice during late pregnancy is sufficient to decrease pup survival and induce anxiety-like and depression-like behaviors in the offspring. Further, the abnormal behaviors in juvenile mice reared by GABRD−/− mice are alleviated by treatment of the mothers with the corticotropin-releasing hormone (CRH) antagonist, Antalarmin. These studies suggest that hyperresponsiveness of the HPA axis is associated with postpartum depression and may mediate the adverse effects of maternal depression on offspring behavior.

  • In vitro gamma oscillations following partial and complete ablation of δ subunit-containing GABAA receptors from parvalbumin interneurons.
    Neuropharmacology, 2014
    Co-Authors: Isabella Ferando, Istvan Mody
    Abstract:

    Perisynaptic and extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) mediate tonic conductances in many neurons. On principal cells of the neocortex and hippocampus they comprise α4 subunits, whereas they usually contain α1 on various interneurons. Specific characteristics of δ-GABAARs are their pharmacology and high plasticity. In particular δ-GABAARs are sensitive to low concentrations of neurosteroids (NS) and during times of altered NS production (stress, puberty, ovarian cycle and pregnancy) δ-GABAARs expression varies in many neurons regardless of the α subunits they contain, with direct consequences for neuronal excitability and network synchrony. For example δ-GABAARs plasticity on INs underlies modifications in hippocampal γ oscillations during pregnancy or over the ovarian cycle. Most δ-GABAAR-expressing INs in CA3 stratum pyramidale (SP) are parvalbumin (PV) + INs, whose fundamental role in γ oscillations generation and control has been extensively investigated. In this study we reduced or deleted δ-subunits in PV + INs, with the use of a PV/Cre-GABRD/floxed genetic system. We find that in vitro CA3 γ oscillations of both PV-GABRD(+/-)and PV-GABRD(-/-) mice are characterized by higher frequencies than WT controls. The increased frequencies could be lowered to control levels in PV-GABRD(+/-) by the NS allopregnanolone (3α,5α-tetrahydroprogesterone, 100 nM) but not the synthetic δ-GABAAR positive allosteric modulator 4-Chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl] benzamide (DS-2, 10 μM). This is consistent with the idea that DS-2, in contrast to ALLO, selectively targets α4/δ-GABAARs but not the α1/δ-GABAARs found on INs. Therefore, development of drugs selective for IN-specific α1/δ-GABAARs may be useful in neurological and psychiatric conditions correlated with altered PV + IN function and aberrant γ oscillations.

  • Neuron Report GABAAR Plasticity during Pregnancy: Relevance to Postpartum Depression
    2011
    Co-Authors: Jamie Maguire, Istvan Mody
    Abstract:

    Fluctuating neurosteroid levels over the ovarian cycle modulate neuronal excitability through effects on GABAA receptors (GABAARs). The large increase in progesterone-derived neurosteroids during pregnancy and their precipitous decline at parturition may have considerable effects on GABAARs during pregnancy and postpartum. Here we show a significant decrease in tonic and phasic inhibitions in pregnant mice, mediated by a downregulation of GABAAR d and g2 subunits, respectively, which rebounds immediately postpartum. Mice which do not exhibit GABAAR d subunit regulation throughout pregnancy (GABRD + / and GABRD /) exhibit depression-like and abnormal maternal behaviors, resulting in reduced pup survival. These abnormal postpartum behaviors were ameliorated in GABRD +/ mice by a GABAAR d-subunit-selective agonist, THIP. We suggest that GABRD +/ and GABRD / mice constitute a mouse model of postpartum depression that may be useful for evaluating potential therapeutic interventions

  • Developmental regulation and neuroprotective effects of striatal tonic GABAA currents.
    Neuroscience, 2010
    Co-Authors: Vijayalakshmi Santhakumar, R.t. Jones, Istvan Mody
    Abstract:

    Striatal neurons are known to express GABAA receptor subunits that underlie both phasic and tonic inhibition. Striatal projection neurons, or medium spiny neurons (MSNs), are divided into two classes: MSNs containing the dopamine D1 receptor (D1-MSNs) form the direct pathway to the substantia nigra and facilitate movement while MSNs expressing the dopamine D2 receptor (D2-MSNs) form the pallidal pathway that inhibits movement. Consequently, modulating inhibition in distinct classes of MSNs will differentially impact downstream network activity and motor behavior. Given the powerful role of extrasynaptic inhibition in controlling neuronal excitability, we examined the nature of striatal tonic inhibition and its potential role in preventing excitotoxicity. Consistent with earlier studies in young (P16–P25) mice, tonic GABA currents in D2-MSNs were larger than in D1-MSNs. However, with age (>P30 mice) the tonic GABA currents increased in D1-MSNs but decreased in D2-MSNs. These data demonstrate a developmental switch in the MSN subtype expressing larger tonic GABA currents. Compared to wild-type, MSNs from adult mice lacking the GABAAR δ subunit (GABRD−/− mice) had both decreased tonic GABA currents and reduced survival following an in vitro excitotoxic challenge with quinolinic acid. Furthermore, muscimol-induced tonic GABA currents were accompanied by reduced acute swelling of striatal neurons after exposure to NMDA in WT mice but not in GABRD−/− mice. Our data are consistent with a role for tonic inhibition mediated by GABAAR δ subunits in neuroprotection against excitotoxic insults in the adult striatum.

  • gaba a r plasticity during pregnancy relevance to postpartum depression
    Neuron, 2008
    Co-Authors: Jamie Maguire, Istvan Mody
    Abstract:

    Fluctuating neurosteroid levels over the ovarian cycle modulate neuronal excitability through effects on GABA(A) receptors (GABA(A)Rs). The large increase in progesterone-derived neurosteroids during pregnancy and their precipitous decline at parturition may have considerable effects on GABA(A)Rs during pregnancy and postpartum. Here we show a significant decrease in tonic and phasic inhibitions in pregnant mice, mediated by a downregulation of GABA(A)R delta and gamma2 subunits, respectively, which rebounds immediately postpartum. Mice which do not exhibit GABA(A)R delta subunit regulation throughout pregnancy (GABRD(+/-) and GABRD(-/-)) exhibit depression-like and abnormal maternal behaviors, resulting in reduced pup survival. These abnormal postpartum behaviors were ameliorated in GABRD(+/-) mice by a GABA(A)R delta-subunit-selective agonist, THIP. We suggest that GABRD(+/-) and GABRD(-/-) mice constitute a mouse model of postpartum depression that may be useful for evaluating potential therapeutic interventions.

Jamie Maguire - One of the best experts on this subject based on the ideXlab platform.

  • Female-specific decreases in alcohol binge-like drinking resulting from GABA A receptor delta-subunit knockdown in the VTA
    Scientific reports, 2019
    Co-Authors: L. M. Darnieder, Laverne C. Melón, N. L. Walton, K. A. Miczek, Jamie Maguire
    Abstract:

    Binge drinking is short-term drinking that achieves blood alcohol levels of 0.08 g/dl or above. It exhibits well-established sex differences in GABAergic inhibitory neurotransmission, including extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) that mediate tonic inhibition, or synaptic γ2-containing GABAARs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate δ-GABAARs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic δ-GABAARs to male and female binge-like drinking in a critical area of mesolimbic circuitry—the ventral tegmental area (VTA). Quantitative PCR revealed higher GABRD transcript levels and larger tonic currents in the VTA of females compared to males. In contrast, male and female Gabrg2 transcript levels and measures of phasic inhibition were equivalent. Intra-VTA infusion of AAV-Cre-GFP in floxed GABRD mice downregulated δ-GABAARs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABAAR γ2 subunit reduction in the VTA following AAV-Cre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABAAR subunit specificity in alcohol intake.

  • A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression
    Frontiers Media S.A., 2018
    Co-Authors: Laverne Melón, Rebecca Hammond, Mike Lewis, Jamie Maguire
    Abstract:

    Preclinical testing of treatments for postpartum depression (PPD) has been limited due to the lack of available animal models of such a complex disorder. To address this limitation, our laboratory has generated unique preclinical mouse models that exhibit abnormal postpartum behaviors. Mice with a loss or reduction in the expression of the GABAA receptor (GABAAR) δ subunit (GABRD−/− or GABRD+/−, respectively) and mice that lack the K+/Cl− co-transporter, KCC2, specifically in corticotropin-releasing hormone (CRH) neurons (KCC2/Crh mice) exhibit depression-like behaviors restricted to the postpartum period and deficits in maternal care, which serve as useful tools for testing novel therapeutic compounds. Utilizing these preclinical models, we tested the ability of a novel, synthetic, neuroactive steroid developed by SAGE Therapeutics, SGE-516, to improve abnormal postpartum behaviors. GABRD−/−, GABRD+/−, and KCC2/Crh dams treated with SGE-516 (450 mg/kg chow) during late pregnancy exhibit a decrease in depression-like behaviors and improvements in maternal care at 48 h postpartum. Interestingly, acute treatment with SGE-516 also exhibits robust therapeutic effects in these preclinical PPD models. We previously discovered abnormal stress reactivity associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with depression-like behaviors in the preclinical PPD models, evident from an increase in stress-induced corticosterone levels and dephosphorylation and downregulation of KCC2 in the paraventricular nucleus of the hypothalamus (PVN) during the peripartum period. Here we demonstrated that SGE-516 treatment is sufficient to prevent the stress-induced increase in corticosterone and dephosphorylation and downregulation of KCC2 in the PVN. In contrast, and consistent with the distinct pharmacology of SGE-516 compared to benzodiazepines, treatment with clobazam (250 mg/kg chow) did not alter the depression-like phenotype or deficits in maternal care observed in these preclinical models of PPD. These findings are consistent with the positive double-blind, randomized, placebo-controlled trial findings of a similar compound, brexanolone, in the treatment of patients with postpartum depression. Further, these findings validate the use of these preclinical models of PPD for screening novel compounds for the treatment of postpartum depression

  • Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors
    Epilepsy & behavior : E&B, 2017
    Co-Authors: Andrew Hooper, Rumzah Paracha, Jamie Maguire
    Abstract:

    Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (GABRD/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). GABRD/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, GABRD/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic GABRD/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre-/- littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating GABRD/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.

  • Behavioral Deficits in Juveniles Mediated by Maternal Stress Hormones in Mice
    Neural plasticity, 2015
    Co-Authors: Jamie Maguire, Istvan Mody
    Abstract:

    Maternal depression has been shown to negatively impact offspring development. Investigation into the impact of maternal depression and offspring behavior has relied on correlative studies in humans. Further investigation into the underlying mechanisms has been hindered by the lack of useful animal models. We previously characterized a mouse model which exhibits depression-like behaviors restricted to the postpartum period and abnormal/fragmented maternal care (GABRD−/− mice). Here we utilized this unique mouse model to investigate the mechanism(s) through which maternal depression-like behaviors adversely impact offspring development. Cross-fostering experiments reveal increased anxiety-like and depression-like behaviors in mice reared by GABRD−/− mothers. Wild type and GABRD−/− mice subjected to unpredictable stress during late pregnancy exhibit decreased pup survival and depression-like behavior in the postpartum period. Exogenous corticosterone treatment in wild type mice during late pregnancy is sufficient to decrease pup survival and induce anxiety-like and depression-like behaviors in the offspring. Further, the abnormal behaviors in juvenile mice reared by GABRD−/− mice are alleviated by treatment of the mothers with the corticotropin-releasing hormone (CRH) antagonist, Antalarmin. These studies suggest that hyperresponsiveness of the HPA axis is associated with postpartum depression and may mediate the adverse effects of maternal depression on offspring behavior.

  • Loss of GABRD in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors.
    Psychoneuroendocrinology, 2013
    Co-Authors: Vallent Lee, Jhimly Sarkar, Jamie Maguire
    Abstract:

    The hypothalamic-pituitary-adrenal (HPA) axis is under tight regulation by strong GABAergic inhibition onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. CRH neurons receive two forms of GABAergic inhibition, phasic and tonic, but the specific roles of these two types of signaling have not yet been studied in this cell type. Our lab recently demonstrated a role for the GABAAR δ subunit in the tonic GABAergic regulation of CRH neurons. Using a floxed GABRD mouse model established in our laboratory, we generated mice in which the GABAAR δ subunit is selectively removed from CRH neurons (GABRD/Crh mice), resulting in a loss of tonic GABAergic inhibition in these neurons. Interestingly, the loss of this tonic GABAergic constraint did not significantly alter basal levels of corticosterone (CORT). However, the loss of the GABAAR δ subunit in CRH neurons blunted the CORT response to stress, likely due to the loss of the disinhibitory effect of GABA following acute stress. This blunting of HPA axis reactivity was associated with a decrease in depression-like and anxiety-like behaviors. Exogenous CORT was sufficient to increase anxiety-like and depression-like behaviors in GABRD/Crh mice. Together, these results show the importance of the GABAAR δ subunit in the regulation of CRH neurons, and thus the HPA axis, and demonstrate that dysregulation of CRH neurons alters stress-related behaviors.

M. Louise Tierney - One of the best experts on this subject based on the ideXlab platform.

  • Sperm gamma-aminobutyric acid type A receptor delta subunit (GABRD) and its interaction with purinergic P2X2 receptors in progesterone-induced acrosome reaction and male fertility.
    Reproduction fertility and development, 2017
    Co-Authors: Ke Wang, Yan Chen, Xiao Tong Liang, Huanxun Yue, M. Louise Tierney
    Abstract:

    The mechanism underlying the non-genomic action of progesterone in sperm functions and related Ca2+ mobilisation remains elusive. Herein we report the expression of gamma-aminobutyric acid type A receptor delta subunit (GABRD) in human and rodent sperm and its involvement in mediating the progesterone-induced acrosome reaction. GABRD was localised in the sperm head/neck region. A δ(392-422)-specific inhibitory peptide against GABRD blocked the progesterone-induced acrosome reaction and the associated increase in intracellular Ca2+. Similarly, an inhibitory effect against both progesterone-induced Ca2+ influx and the acrosome reaction was observed with a P2X2 receptor antagonist. The lack of synergism between the GABRD and P2X2 inhibitors suggests that these two receptors are playing a role in the same pathway. Furthermore, a co-immunoprecipitation experiment demonstrated that GABRD could undergo protein-protein interactions with the Ca2+-conducting P2X2 receptor. This interaction between the receptors could be reduced following progesterone (10μM) inducement. Significantly reduced GABRD expression was observed in spermatozoa from infertile patients with reduced acrosome reaction capacity, suggesting that normal expression of GABRD is critical for the sperm acrosome reaction and thus male fertility. The results of the present study indicate that GABRD represents a novel progesterone receptor or modulator in spermatozoa that is responsible for the progesterone-induced Ca2+ influx required for the acrosome reaction through its interaction with the P2X2 receptor.

Beverley A. Orser - One of the best experts on this subject based on the ideXlab platform.

  • δ-Subunit Containing GABA A Receptors Modulate Respiratory Networks
    Scientific reports, 2017
    Co-Authors: Gaspard Montandon, Beverley A. Orser, Hattie Liu, Richard L. Horner
    Abstract:

    Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAA receptors (δGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function in the preBotzinger Complex (preBotC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBotC δGABAARs in anesthetized rats and wild-type mice decreased breathing rate. In δGABAAR knockout (GABRD -/-) mice, however, δGABAARs activation had no effect on breathing rate. We then found that during active wakefulness associated with behaviors and movements, diaphragm activation was higher in the GABRD -/- compared to wild-type mice, but not in other states. These findings identify that δGABAARs modulate the respiratory network, which is critical to understand how δGABAARs change breathing in pathological conditions affecting extra-synaptic GABAA receptor function such as exposure to anesthetics and neurosteroids.

  • δGABAA Receptors Are Necessary for Synaptic Plasticity in the Hippocampus: Implications for Memory Behavior.
    Anesthesia and analgesia, 2016
    Co-Authors: Paul D. Whissell, Sinziana Avramescu, Dian-shi Wang, Beverley A. Orser
    Abstract:

    BACKGROUND Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) contribute to memory performance. Dysregulation of δGABAA receptor expression, which occurs in some neurological disorders, is associated with memory impairment. Mice lacking δGABAA receptors (GABRD) exhibit deficits in their ability to distinguish between similar memories, a process which is referred to as pattern separation. The CA3 and dentate gyrus subfields of the hippocampus regulate pattern separation, raising the possibility that synaptic plasticity is impaired in these regions in GABRD mice. Although long-term potentiation (LTP), the most widely studied form of synaptic plasticity, is normal in the dentate gyrus of GABRD mice, LTP in the CA3 subfield has not been studied. Here, we tested the hypothesis that LTP is reduced in the CA3 subfield of GABRD mice. METHODS LTP of extracellular field postsynaptic potentials was studied in the mossy fiber (MF)-CA3 pathway using hippocampal slices from GABRD and wild-type (WT) mice. We also examined paired pulse responses and input-output relationships at MF-CA3 synapses. RESULTS MF-CA3 LTP was reduced in GABRD mice, as evidenced by decreased potentiation of field postsynaptic potentials (WT: 178.3% ± 16.1% versus GABRD: 126.3% ± 6.9%; P = 0.0091). Thus, the deletion of δGABAA receptors is associated with impaired plasticity. Bicuculline (BIC), a GABAA receptor antagonist, reduced plasticity in WT but not in GABRD mice (WT + BIC: 123.9% ± 7.6% versus GABRD + BIC: 136.5% ± 7.0%). Paired pulse responses and input-output relationships did not differ between the genotypes (all Ps > 0.05). CONCLUSIONS Both genetic deletion and pharmacological blockade of δGABAA receptors impair MF-CA3 LTP, suggesting that δGABAA receptors are necessary for synaptic plasticity in the CA3 subfield. Drugs that enhance δGABAA receptor function may reverse deficits in synaptic plasticity in the CA3 subfield and improve pattern separation in neurological disorders.

  • Acutely increasing δGABAA receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus
    Frontiers in neural circuits, 2013
    Co-Authors: Paul D. Whissell, Dian-shi Wang, Irene Lecker, Dave Eng, Loren J. Martin, Beverley A. Orser
    Abstract:

    Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor–preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABAA receptor null mutant (GABRD–/–) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not GABRD–/– mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not GABRD–/– mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity.

  • γ-aminobutyric acid type A receptors that contain the δ subunit promote memory and neurogenesis in the dentate gyrus
    Annals of neurology, 2013
    Co-Authors: Paul D. Whissell, Dian-shi Wang, Shira Rosenzweig, Irene Lecker, J. Martin Wojtowicz, Beverley A. Orser
    Abstract:

    Objective Extrasynaptic γ-aminobutyric acid type A receptors that contain the δ subunit (δGABAA receptors) are highly expressed in the dentate gyrus (DG) subfield of the hippocampus, where they generate a tonic conductance that regulates neuronal activity. GABAA receptor-dependent signaling regulates memory and also facilitates postnatal neurogenesis in the adult DG; however, the role of the δGABAA receptors in these processes is unclear. Accordingly, we sought to determine whether δGABAA receptors regulate memory behaviors, as well as neurogenesis in the DG. Methods Memory and neurogenesis were studied in wild-type (WT) mice and transgenic mice that lacked δGABAA receptors (GABRD−/−). To pharmacologically increase δGABAA receptor activity, mice were treated with the δGABAA receptor-preferring agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP). Behavioral assays including recognition memory, contextual discrimination, and fear extinction were used. Neurogenesis was studied by measuring the proliferation, survival, migration, maturation, and dendritic complexity of adult-born neurons in the DG. Results GABRD−/− mice exhibited impaired recognition memory and contextual discrimination relative to WT mice. Fear extinction was also impaired in GABRD−/− mice, although the acquisition of fear memory was enhanced. Neurogenesis was disrupted in GABRD−/− mice as the migration, maturation, and dendritic development of adult-born neurons were impaired. Long-term treatment with THIP facilitated learning and neurogenesis in WT but not GABRD−/− mice. Interpretation δGABAA receptors promote the performance of certain DG-dependent memory behaviors and facilitate neurogenesis. Furthermore, δGABAA receptors can be pharmacologically targeted to enhance these processes. Ann Neurol 2013;74:611–621

  • Pharmacological enhancement of δ-subunit-containing GABAA receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice
    Pain, 2011
    Co-Authors: Robert P. Bonin, Paul D. Whissell, Charalampos Labrakakis, David G. Eng, Yves De Koninck, Beverley A. Orser
    Abstract:

    Abstract The development of new strategies for the treatment of acute pain requires the identification of novel nonopioid receptor targets. This study explored whether δ-subunit-containing GABA A Rs (δGABA A Rs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether δGABA A R activity regulates acute nociception. Whole-cell recordings revealed that δGABA A Rs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. Increasing δGABA A R function by applying the δGABA A R-preferring agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP) increased the tonic current and inhibited neuronal excitability in spinal neurons from wild-type (WT) but not δ subunit null-mutant ( GABRD −/− ) mice. In behavioral studies, baseline δGABA A R activity did not regulate acute nociception; however, THIP administered intraperitoneally or intrathecally attenuated acute nociception in WT but not GABRD −/− mice. In the formalin nociception assay, the phase 1 response was similar for WT and GABRD −/− mice. In contrast, the phase 2 response, which models central sensitization, was greater in GABRD −/− mice than WT. THIP administered intraperitoneally or intrathecally inhibited phase 1 responses of WT but not GABRD −/− mice and had no effect on phase 2 responses of WT mice. Surprisingly, THIP reduced the enhanced phase 2 response in GABRD −/− mice. Together, these results suggest that δGABA A Rs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization.

Ke Wang - One of the best experts on this subject based on the ideXlab platform.

  • Sperm gamma-aminobutyric acid type A receptor delta subunit (GABRD) and its interaction with purinergic P2X2 receptors in progesterone-induced acrosome reaction and male fertility.
    Reproduction fertility and development, 2017
    Co-Authors: Ke Wang, Yan Chen, Xiao Tong Liang, Huanxun Yue, M. Louise Tierney
    Abstract:

    The mechanism underlying the non-genomic action of progesterone in sperm functions and related Ca2+ mobilisation remains elusive. Herein we report the expression of gamma-aminobutyric acid type A receptor delta subunit (GABRD) in human and rodent sperm and its involvement in mediating the progesterone-induced acrosome reaction. GABRD was localised in the sperm head/neck region. A δ(392-422)-specific inhibitory peptide against GABRD blocked the progesterone-induced acrosome reaction and the associated increase in intracellular Ca2+. Similarly, an inhibitory effect against both progesterone-induced Ca2+ influx and the acrosome reaction was observed with a P2X2 receptor antagonist. The lack of synergism between the GABRD and P2X2 inhibitors suggests that these two receptors are playing a role in the same pathway. Furthermore, a co-immunoprecipitation experiment demonstrated that GABRD could undergo protein-protein interactions with the Ca2+-conducting P2X2 receptor. This interaction between the receptors could be reduced following progesterone (10μM) inducement. Significantly reduced GABRD expression was observed in spermatozoa from infertile patients with reduced acrosome reaction capacity, suggesting that normal expression of GABRD is critical for the sperm acrosome reaction and thus male fertility. The results of the present study indicate that GABRD represents a novel progesterone receptor or modulator in spermatozoa that is responsible for the progesterone-induced Ca2+ influx required for the acrosome reaction through its interaction with the P2X2 receptor.