| 1. |
- Das, Roshni, et al.
(författare)
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Medroxyprogesterone acetate positively modulates specific GABAA-receptor subtypes - affecting memory and cognition
- 2022
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 141
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Tidskriftsartikel (refereegranskat)abstract
- Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the progesterone metabolite allopregnanolone, have GABAA-receptor modulatory effects and are known to affect memory, learning, appetite, and mood. In women, 4 years chronic treatment with MPA doubles the frequency of dementia and in rats, MPA causes cognitive impairment related to the GABAergic system. Activation of the membrane bound GABAA receptor results in a chloride ion flux that can be studied by whole-cell patch-clamp electrophysiological recordings. The purpose of this study was to clarify the modulatory effects of MPA and specific MPA metabolites, with structures like known GABAA-receptor modulators, on different GABAA-receptor subtypes. An additional aim was to verify the results as steroid effects on GABA response in single cells taken from rat hypothalamus. HEK-293 cell-lines permanently expressing the recombinant human GABAA-receptor subtype α1β2γ2L or α5β3γ2L or α2β3γ2S were created. The MPA metabolites 3α5α-MPA,3β5α-MPA and 3β5β-MPA were synthesised and purified for electrophysiological patch-clamp measurements with a Dynaflow system. The effects of MPA and tetrahydrodeoxycorticosterone were also studied. None of the studied MPA metabolites affected the responses mediated by α1β2γ2L or α5β3γ2L GABAA receptors. Contrary, MPA clearly acted both as a positive modulator and as a direct activator of the α5β3γ2L and α2β3γ2S GABAA receptors. However, in concentrations up to 10 μM, MPA was inactive at the α1β2γ2L GABAA receptor. In the patch-clamp recordings from dissociated cells of the preoptic area in rats, MPA increased the amplitude of responses to GABA. In addition, MPA alone without added GABA, evoked a current response. In conclusion, MPA acts as a positive modulator of specific GABAA receptor subtypes expressed in HEK cells and at native GABA receptors in single cells from the hypothalamic preoptic area.
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| 4. |
- Kotikova, Marie R., et al.
(författare)
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Shunting effect of synaptic channels located on presynaptic terminal
- 2023
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Ingår i: Advances in neural computation, machine learning, and cognitive research VI. - Cham : Springer Science and Business Media Deutschland GmbH. - 9783031190315 ; , s. 223-230
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Konferensbidrag (refereegranskat)abstract
- Experiments show that GABAA receptors located on an axon can affect synaptic transmission, presumably through modulation of calcium influx on a presynaptic terminal which determines release of mediator. In this paper, a mathematical model that describes the shunting effect of these receptors on the presynaptic calcium influx is proposed. Simulations show that the effect of GABAA channels depends on their location and reversal potential that is determined by the concentration of chloride accumulated inside the axon. The synaptic channels located in the center of axon cannot stop the propagation of action potential thus not affecting the calcium influx, regardless of the value of the reversal potential. If the receptors are located at the end of the axon, they can influence on the mediator release by means of either the inactivation of calcium channels located on the terminal or the decrease of action potential amplitude, depending on the inactivation thresholds of calcium and sodium channels. In the both cases, the effect is noticeable only for depolarized GABAA reversal potential, i.e. in the conditions of chloride accumulation. Overall, the simulations clarify possible role of GABAA receptors and chloride accumulation on synaptic transmission.
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| 5. |
- Malinina, Evgenya, 1972-, et al.
(författare)
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Differential control of spontaneous and evoked GABA release by presynaptic L-type Ca2+ channels in the rat medial preoptic nucleus
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- To clarify the role of presynaptic L-type Ca2+ channels in GABA-mediated transmission in the medial preoptic nucleus (MPN), spontaneous as well as impulse-evoked inhibitory postsynaptic currents (sIPSCs and eIPSCs, respectively) were recorded from MPN neurons in a slice preparation from rat brain. The effects of different stimulus protocols and pharmacological tools to detect contributions of L-type Ca2+ channels and of Ca2+-activated K+ (KCa) channels were analysed. Block of L-type channels did not affect the sIPSCs properties (frequency, amplitude, decay time course) in the absence of external stimulation, but unexpectedly potentiated the eIPSCs evoked at low stimulus frequency (0.1 – 2.0 Hz). This effect was similar to and overlapping with the effect of KCa-channel blockers. High-frequency stimulation (50 Hz for 10 s) induced a substantial post-tetanic potentiation (PTP) of the eIPSC amplitude as well as of the sIPSC frequency. Block of L-type channels still potentiated the eIPSC during PTP, but in contrast reduced the sIPSC frequency during PTP. It was concluded that L-type channels provide a means for differential control of spontaneous and impulse-evoked GABA release and that this differential control is prominent during short-term synaptic plasticity. Functional coupling of the presynaptic L-type channels to KCa channels explains the observed effects on eIPSCs.
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| 6. |
- Song, Inseon, et al.
(författare)
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Heparan sulfates regulate axonal excitability and context generalization through CA2+/Calmodulin-dependent protein kinase II
- 2023
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 h after injection in mice. Patch clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 h after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting the key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories.
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| 7. |
- Yelhekar, Tushar D., 1984-, et al.
(författare)
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How to Properly Measure a Current-Voltage Relation? -Interpolation vs. Ramp Methods Applied to Studies of GABA(A) Receptors
- 2016
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The relation between current and voltage, I-V relation, is central to functional analysis of membrane ion channels. A commonly used method, since the introduction of the voltage-clamp technique, to establish the I-V relation depends on the interpolation of current amplitudes recorded at different steady voltages. By a theoretical computational approach as well as by experimental recordings from GABA(A) receptor mediated currents in mammalian central neurons, we here show that this interpolation method may give reversal potentials and conductances that do not reflect the properties of the channels studied under conditions when ion flux may give rise to concentration changes. Therefore, changes in ion concentrations may remain undetected and conclusions on changes in conductance, such as during desensitization, may be mistaken. In contrast, an alternative experimental approach, using rapid voltage ramps, enable I-V relations that much better reflect the properties of the studied ion channels.
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| 9. |
- Zhuravleva, Z.D., et al.
(författare)
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Choosing the optimal rat stock as a model for research into pharmacological correction of male sexual dysfunction
- 2021
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Ingår i: Sovremennye Tehnologii v Medicine. - : Privolzhsky Research Medical University. - 2076-4243. ; 13:6, s. 36-41
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study is to identify the mechanisms mediating differences in sexual behavior between Sprague Dawley and Wistar rats, in order to choose the optimal stock for research into pharmacological correction of male sexual dysfunction. Materials and Methods. The experiments were carried out on sexually mature male rats of two stocks (Sprague Dawley and Wistar) weighing 350–450 g and aged 3 to 6 months. The comparative study of animal behavior was performed using standard tests for social interaction, locomotor activity, and anxiety level, as well as male mating behavior patterns. In order to determine the role of hypothalamic glycine receptors in the male sexual behavior, pharmacological manipulations of glycine receptor activity during mating with receptive females were conducted via bilateral intracerebral microcannulas implanted in the medial preoptic area (mPOA) of the male rat anterior hypothalamus. Results. The obtained results revealed statistically significant inter-stock differences in sexual behavior at the final consummatory stage of both intact animals and those after pharmacological activation of glycine receptors in the mPOA. The number of anxiety-related grooming patterns in the Open Field test significantly differed between the stocks for both intact animals and those after pharmacological activation of glycine receptors; the observed differences disappeared after the mPOA glycine receptors were blocked. In the Crowley test of social interaction, no significant difference was found between the stocks. Thus, the revealed difference in sexual behavior between Sprague Dawley and Wistar male rats is likely due to the difference in the level of anxiety, which, in turn, may be associated with difference in the mechanisms of glycinergic neurotransmission in the hypothalamic mPOAs of these rats. Conclusion. To study the relationship between the level of anxiety and sexual behavior, the choice of the Wistar rat stock is optimal since the male sexual behavior in this stock is more sensitive to stress than that in Sprague Dawley rats. However, to model male sexual dysfunction not associated with anxiety, the use of Sprague Dawley male rats should be preferred as these animals show more stable sexual behavior, which is less dependent on the level of anxiety.
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| 10. |
- Zhuravleva, Z. D., et al.
(författare)
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Effects of Glycine Receptors of the Medial Preoptic Nucleus on Sexual Behavior of Male Wistar Rats
- 2020
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Ingår i: Bulletin of experimental biology and medicine. - : Springer. - 0007-4888 .- 1573-8221. ; 169:3, s. 299-301
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Tidskriftsartikel (refereegranskat)abstract
- We studied the effect of bilateral microinjections of selective pharmacological agents modulating glycine receptor activity into the medial preoptic nucleus on sexual behavior of male Wistar rats. Application of the glycine receptor blocker strychnine (20 μM, 2 μl) led to a significant inhibition of both appetitive and consummatory components of sexual behavior, whereas stimulation with glycine (1 mM and 50 μM, 2 μl) had no significant effect.
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