scholarly journals Plasticity of GABAA Receptors during Pregnancy and Postpartum Period: From Gene to Function

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Valentina Licheri ◽  
Giuseppe Talani ◽  
Ashish A. Gorule ◽  
Maria Cristina Mostallino ◽  
Giovanni Biggio ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Postpartum Period ◽  
Neuronal Excitability ◽  
Receptor Expression ◽  
Neuroactive Steroids ◽  
Receptor Function ◽  
Pregnancy And Postpartum ◽  
Sudden Decrease ◽  
New Treatments

Pregnancy needs complex pathways that together play a role in proper growth and protection of the fetus preventing its premature loss. Changes during pregnancy and postpartum period include the manifold machinery of neuroactive steroids that plays a crucial role in neuronal excitability by local modulation of specific inhibitory receptors: the GABAA receptors. Marked fluctuations in both blood and brain concentration of neuroactive steroids strongly contribute to GABAA receptor function and plasticity. In this review, we listed several interesting results regarding the regulation and plasticity of GABAA receptor function during pregnancy and postpartum period in rats. The increase in brain levels of neuroactive steroids during pregnancy and their sudden decrease immediately before delivery are causally related to changes in the expression/function of specific GABAA receptor subunits in the hippocampus. These data suggest that alterations in GABAA receptor expression and function may be related to neurological and psychiatric disorders associated with crucial periods in women. These findings could help to provide potential new treatments for these women’s disabling syndromes.

scholarly journals Neuronal Hyperexcitability and Reduction of GABAA-Receptor Expression in the Surround of Cerebral Photothrombosis

1996 ◽  
Vol 16 (5) ◽  
pp. 906-914 ◽  
Author(s):  
Klaus Schiene ◽  
Claus Bruehl ◽  
Karl Zilles ◽  
Meishu Qu ◽  
Georg Hagemann ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Rose Bengal ◽  
Sensorimotor Cortex ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Brain Areas ◽  
Series Of Experiments ◽  
The Rose

Changes of neuronal excitability and γ-aminobutyric acid (GABAA)-receptor expression were studied in the surround of photothrombotic infarcts, which were produced in the sensorimotor cortex of the rat by using the rose bengal technique. In a first series of experiments, multiunit recordings were performed on anesthetized animals 2–3 mm lateral from the lesion. Mean discharge frequency was considerably higher in recordings from lesioned animals (>100 Hz in the first postlesional week) compared with control animals (mean, 15 Hz). These alterations were already present after 1 day but were most pronounced 3 to 7 days after lesion induction. Thereafter the hyperexcitability declined again, although it remained visible up to 4 months. In a second series of experiments, the GABAA-receptor expression was studied autoradiographically. This revealed a reduction of GABAA receptors in widespread brain areas ipsilateral to the lesion. The reduction was most pronounced in the first days after lesion induction and declined with longer intervals. It is concluded that cortical infarction due to photothrombosis leads to a long-lasting and widespread reduction of GABAA-receptor expression in the surround of the lesion, which is associated with an increased neuronal excitability. Such alterations may be responsible for epileptic seizures that can be observed in some patients after stroke and may contribute to neurologic deficits after stroke.

Chapter 6 GABAA Receptor Function and Gene Expression During Pregnancy and Postpartum

2009 ◽  
pp. 73-94 ◽  
Author(s):  
Giovanni Biggio ◽  
Maria Cristina Mostallino ◽  
Paolo Follesa ◽  
Alessandra Concas ◽  
Enrico Sanna
Keyword(s):  
Gene Expression ◽  
Gabaa Receptor ◽  
Receptor Function ◽  
Pregnancy And Postpartum

scholarly journals Characterization of a Novel Tonic γ-Aminobutyric AcidA Receptor-Mediated Inhibition in Magnocellular Neurosecretory Neurons and Its Modulation by Glia

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3746-3760 ◽  
Author(s):  
Jin Bong Park ◽  
Silvia Skalska ◽  
Javier E. Stern
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Neuronal Excitability ◽  
Tonic Inhibition ◽  
Synaptic Activity ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Gaba Transporters ◽  
Neurosecretory Neurons ◽  
Vasopressin Neurons

In addition to mediating conventional quantal synaptic transmission (also known as phasic inhibition), γ-aminobutyric acidA (GABAA) receptors have been recently shown to underlie a slower, persistent form of inhibition (tonic inhibition). Using patch-clamp electrophysiology and immunohistochemistry, we addressed here whether a GABAA receptor-mediated tonic inhibition is present in supraoptic nucleus (SON) neurosecretory neurons; identified key modulatory mechanisms, including the role of glia; and determined its functional role in controlling SON neuronal excitability. Besides blocking GABAA-mediated inhibitory postsynaptic currents, the GABAA receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (Itonic), both in oxytocin and vasopressin neurons. Conversely, the high-affinity antagonist gabazine selectively blocked inhibitory postsynaptic currents. Under basal conditions, Itonic was independent on the degree of synaptic activity but was strongly modulated by the activity GABA transporters (GATs), mostly the GAT3 isoform, found here to be localized in SON glial cells/processes. Extracellular activation of GABAergic afferents evoked a small gabazine-insensitive, bicuculline-sensitive current, which was enhanced by GAT blockade. These results suggest that Itonic may be activated by spillover of GABA during conditions of strong and/or synchronous synaptic activity. Blockade of Itonic increased input resistance, induced membrane depolarization and firing activity, and enhanced the input-output function of SON neurons. In summary, our results indicate that GABAA receptors, possibly of different molecular configuration and subcellular distribution, mediate synaptic and tonic inhibition in SON neurons. The latter inhibitory modality plays a major role in modulating SON neuronal excitability, and its efficacy is modulated by the activity of glial GATs.

Neurosteroid modulation of GABAA receptor function by independent action at multiple specific binding sites

2021 ◽  
Vol 19 ◽  
Author(s):  
Lei Wang ◽  
Douglas F. Covey ◽  
Gustav Akk ◽  
Alex S. Evers
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Specific Binding ◽  
Mammalian Brain ◽  
Allosteric Modulators ◽  
Receptor Function ◽  
Functional Effect ◽  
Specific Binding Sites ◽  
Independent Effects ◽  
Endogenous Modulators

: Neurosteroids are endogenous modulators of GABAA receptors that mediate anxiety, pain, mood and arousal. The 3-hydroxyl epimers, allopregnanolone (3α-OH) and epi-allopregnanolone (3β-OH) are both prevalent in mammalian brain and produce opposite effects on GABAA receptor function, acting as positive and negative allosteric modulators respectively. This Perspective provides a model to explain the actions of 3α-OH and 3β-OH neurosteroids. The model is based on evidence that the neurosteroid epimers bind to an overlapping subset of specific sites on GABAA receptors, with their net functional effect on channel gating being the sum of their independent effects at each site.

scholarly journals Social Isolation-Induced Decreases in Both the Abundance of Neuroactive Steroids and GABAA Receptor Function in Rat Brain

2002 ◽  
Vol 75 (2) ◽  
pp. 732-740 ◽  
Author(s):  
Mariangela Serra ◽  
Maria Giuseppina Pisu ◽  
Martino Littera ◽  
Giacomo Papi ◽  
Enrico Sanna ◽  
...  
Keyword(s):  
Rat Brain ◽  
Gabaa Receptor ◽  
Social Isolation ◽  
Neuroactive Steroids ◽  
Receptor Function

Subunit dependent modulation of GABAA receptor function by neuroactive steroids

1999 ◽  
Vol 819 (1-2) ◽  
pp. 75-82 ◽  
Author(s):  
Rajatavo Maitra ◽  
James N Reynolds
Keyword(s):  
Gabaa Receptor ◽  
Neuroactive Steroids ◽  
Receptor Function

Modulation of GABAA receptor function by neuroactive steroids: evidence for heterogeneity of steroid sensitivity of recombinant GABAA receptor isoforms

1998 ◽  
Vol 76 (9) ◽  
pp. 909-920 ◽  
Author(s):  
Rajatavo Maitra ◽  
James N Reynolds
Keyword(s):  
Gabaa Receptor ◽  
Membrane Current ◽  
Neuroactive Steroids ◽  
Maximal Response ◽  
Gamma Aminobutyric Acid ◽  
Receptor Function ◽  
Gamma Subunit ◽  
Receptor Isoforms ◽  
Analgesic Agents ◽  
Gabaa Receptor Isoforms

Neuroactive steroids are potent, selective allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptor function in the central nervous system, and may serve as endogenous anxiolytic and analgesic agents. In order to study the influence of subunit subtypes of the GABAA receptor on modulation of receptor function by neuroactive steroids, we expressed human recombinant GABAA receptors in Xenopus oocytes. GABA-activated membrane current, and the modulatory effects of the endogenous neurosteroid 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone) and the synthetic steroid anesthetic 5alpha-pregnan-3alpha-ol-11,20-dione (alphaxalone) were measured using two-electrode voltage-clamp recording techniques. Allopregnanolone had similar effects to potentiate GABA-activated membrane current in the alpha1beta1gamma2L and alpha1beta2gamma2L receptor isoforms. In contrast, alphaxalone was much more effective as a positive allosteric modulator on the alpha1beta1gamma2L receptor isoform. In the absence of the gamma2L subunit subtype, allopregnanolone had much greater efficacy, but its potency was decreased. Allopregnanolone was much more effective on the alpha1beta1 receptor isoform compared with the alpha1beta2 receptor isoform. The potency for alphaxalone to potentiate the GABA response was not altered in the absence of the gamma2L subunit subtype, although its efficacy was greatly enhanced. Both allopregnanolone and alphaxalone produced nonparallel leftward shifts in the GABA concentration-response relationship in the absence of the gamma2L subunit, decreasing the EC50 concentration of GABA and increasing the maximal response. Only alphaxalone increased the maximal GABA response when the gamma2L subunit subtype was present. The 3beta-pregnane isomers epipregnanolone and isopregnanolone both inhibited the ability of allopregnanolone and alphaxalone to potentiate GABAA receptor function. However, the degree of block produced by the 3beta-pregnane steroid isomers was dependent on the type of receptor isoform studied and the neuroactive steroid tested. Isopregnanolone, the 3beta-isomer of allopregnanolone, was significantly more effective as a blocker of potentiation caused by allopregnanolone compared with alphaxalone in all receptor isoforms tested. Epipregnanolone had a greater efficacy as a blocker at the alpha1beta2gamma2L receptor isoform compared with the alpha1beta1gamma2L receptor isoform, and also produced a greater degree of block of potentiation caused by allopregnanolone compared with alphaxalone. Our results support the hypothesis that the heteromeric assembly of different GABAA receptor isoforms containing different subunit subtypes results in multiple steroid recognition sites on GABAA receptors, which in turn produces distinctly different modulatory interactions between neuroactive steroids acting at the GABAA receptor. The alpha and gamma subunit subtypes may have the greatest influence on allopregnanolone modulation of GABAA receptor function, whereas the beta and gamma subunit subtypes appear to be most important for the modulatory effects of alphaxalone.Key words: GABAA receptor, neurosteroid, allopregnanolone, alphaxalone, Xenopus oocyte.

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