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Amyloid-β induces synaptic dysfunction through G protein-gated inwardly rectifying potassium channels in the fimbria-CA3 hippocampal synapse.

Nava-Mesa MO, Jiménez-Díaz L, Yajeya J, Navarro-Lopez JD - Front Cell Neurosci (2013)

Bottom Line: Aβ perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP.Aβ action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease.In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all Aβ effects previously described.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Neurofisiología y Comportamiento, Facultad de Medicina de Ciudad Real, Universidad de Castilla-La Mancha Ciudad Real, Spain ; Department of Fisiología y Farmacología, Universidad de Salamanca Salamanca, Spain.

ABSTRACT
Last evidences suggest that, in Alzheimer's disease (AD) early stage, Amyloid-β (Aβ) peptide induces an imbalance between excitatory and inhibitory neurotransmission systems resulting in the functional impairment of neural networks. Such alterations are particularly important in the septohippocampal system where learning and memory processes take place depending on accurate oscillatory activity tuned at fimbria-CA3 synapse. Here, the acute effects of Aβ on CA3 pyramidal neurons and their synaptic activation from septal part of the fimbria were studied in rats. A triphasic postsynaptic response defined by an excitatory potential (EPSP) followed by both early and late inhibitory potentials (IPSP) was evoked. The EPSP was glutamatergic acting on ionotropic receptors. The early IPSP was blocked by GABAA antagonists whereas the late IPSP was removed by GABAB antagonists. Aβ perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP. Aβ action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease. In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all Aβ effects previously described. Thus, our findings suggest that Aβ altering GirK channels conductance in CA3 pyramidal neurons might have a key role in the septohippocampal activity dysfunction observed in AD.

No MeSH data available.


Related in: MedlinePlus

Effects of Aβ25–35 perfusion on the response evoked by pharmacological co-activation of GirK channels and GABAB receptors. (A,B) GirK/GABAB postsynaptic hyperpolarization was induced (n = 15) by perfusion of drugs cocktail including TTX (1 μM; voltage-dependent sodium channels blocker), bicuculline (10 μM; specific blocker of GABAA receptors), baclofen (15 μM; agonist of GABAB receptors), and MPD (50 mM; GirK channel agonist) perfusion. Aβ25–35 1.5 μM (n = 3) and 1.0 μM (n = 4)(A and B, respectively) evoked a postsynaptic depolarization. (C) Using the same protocol, Aβ25–35 0.5 μM was not able to produce this depolarization. The cocktail hyperpolarizing effect on membrane potential disappeared after cell washing with bathing solution (n = 4). (D) Tertiapin-Q (n = 4; 0.5 μM; selective blocker of GirK channels), the specific antagonist of GirK channels, induced a depolarization of the postsynaptic hyperpolarization mediated by GirK/GABAB activation, reproducing Aβ25–35 effects. (E) Plot showing the membrane potential changes as a percentage of resting membrane potential (RMP) under pharmacological conditions presented in (A–D). *p < 0.05.
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Figure 9: Effects of Aβ25–35 perfusion on the response evoked by pharmacological co-activation of GirK channels and GABAB receptors. (A,B) GirK/GABAB postsynaptic hyperpolarization was induced (n = 15) by perfusion of drugs cocktail including TTX (1 μM; voltage-dependent sodium channels blocker), bicuculline (10 μM; specific blocker of GABAA receptors), baclofen (15 μM; agonist of GABAB receptors), and MPD (50 mM; GirK channel agonist) perfusion. Aβ25–35 1.5 μM (n = 3) and 1.0 μM (n = 4)(A and B, respectively) evoked a postsynaptic depolarization. (C) Using the same protocol, Aβ25–35 0.5 μM was not able to produce this depolarization. The cocktail hyperpolarizing effect on membrane potential disappeared after cell washing with bathing solution (n = 4). (D) Tertiapin-Q (n = 4; 0.5 μM; selective blocker of GirK channels), the specific antagonist of GirK channels, induced a depolarization of the postsynaptic hyperpolarization mediated by GirK/GABAB activation, reproducing Aβ25–35 effects. (E) Plot showing the membrane potential changes as a percentage of resting membrane potential (RMP) under pharmacological conditions presented in (A–D). *p < 0.05.

Mentions: In order to validate this hypothesis and evaluate the effect of Aβ25–35 on GirK response, we used a GirK channel agonist, MPD (Aryal et al., 2009). Bath application of the previous drugs cocktail together with MPD (50 mM) induced the cell to hyperpolarize by two postsynaptic mechanisms, GABAB receptor activation and direct increase in GirK conductance (Figure 9; −11.2 ± 3.8% of the RMP value; n = 15). Then, perfusion of Aβ25–35 (1–1.5 μM) removed the hyperpolarization mediated by GABAB-GirK stimulation (Figures 9A,E; 5.9 ± 2.7%; n = 3, Figures 9B,E; 4.2 ± 2.4%, n = 4), while this effect was not evident at 0.5 μM (Figures 9C,E; −7.2 ± 4.8% n = 4). In fact, the hyperpolarization could be eliminated when the cocktail was washed (Figure 9C). Finally, Aβ-induced depolarization was mimicked by tertiapin-Q, the specific antagonist of GirK channels (Figures 9D,E; 5.5 ± 1.5%; n = 4), indicating that Aβ25–35 directly affects GirK channels conductance.


Amyloid-β induces synaptic dysfunction through G protein-gated inwardly rectifying potassium channels in the fimbria-CA3 hippocampal synapse.

Nava-Mesa MO, Jiménez-Díaz L, Yajeya J, Navarro-Lopez JD - Front Cell Neurosci (2013)

Effects of Aβ25–35 perfusion on the response evoked by pharmacological co-activation of GirK channels and GABAB receptors. (A,B) GirK/GABAB postsynaptic hyperpolarization was induced (n = 15) by perfusion of drugs cocktail including TTX (1 μM; voltage-dependent sodium channels blocker), bicuculline (10 μM; specific blocker of GABAA receptors), baclofen (15 μM; agonist of GABAB receptors), and MPD (50 mM; GirK channel agonist) perfusion. Aβ25–35 1.5 μM (n = 3) and 1.0 μM (n = 4)(A and B, respectively) evoked a postsynaptic depolarization. (C) Using the same protocol, Aβ25–35 0.5 μM was not able to produce this depolarization. The cocktail hyperpolarizing effect on membrane potential disappeared after cell washing with bathing solution (n = 4). (D) Tertiapin-Q (n = 4; 0.5 μM; selective blocker of GirK channels), the specific antagonist of GirK channels, induced a depolarization of the postsynaptic hyperpolarization mediated by GirK/GABAB activation, reproducing Aβ25–35 effects. (E) Plot showing the membrane potential changes as a percentage of resting membrane potential (RMP) under pharmacological conditions presented in (A–D). *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3722514&req=5

Figure 9: Effects of Aβ25–35 perfusion on the response evoked by pharmacological co-activation of GirK channels and GABAB receptors. (A,B) GirK/GABAB postsynaptic hyperpolarization was induced (n = 15) by perfusion of drugs cocktail including TTX (1 μM; voltage-dependent sodium channels blocker), bicuculline (10 μM; specific blocker of GABAA receptors), baclofen (15 μM; agonist of GABAB receptors), and MPD (50 mM; GirK channel agonist) perfusion. Aβ25–35 1.5 μM (n = 3) and 1.0 μM (n = 4)(A and B, respectively) evoked a postsynaptic depolarization. (C) Using the same protocol, Aβ25–35 0.5 μM was not able to produce this depolarization. The cocktail hyperpolarizing effect on membrane potential disappeared after cell washing with bathing solution (n = 4). (D) Tertiapin-Q (n = 4; 0.5 μM; selective blocker of GirK channels), the specific antagonist of GirK channels, induced a depolarization of the postsynaptic hyperpolarization mediated by GirK/GABAB activation, reproducing Aβ25–35 effects. (E) Plot showing the membrane potential changes as a percentage of resting membrane potential (RMP) under pharmacological conditions presented in (A–D). *p < 0.05.
Mentions: In order to validate this hypothesis and evaluate the effect of Aβ25–35 on GirK response, we used a GirK channel agonist, MPD (Aryal et al., 2009). Bath application of the previous drugs cocktail together with MPD (50 mM) induced the cell to hyperpolarize by two postsynaptic mechanisms, GABAB receptor activation and direct increase in GirK conductance (Figure 9; −11.2 ± 3.8% of the RMP value; n = 15). Then, perfusion of Aβ25–35 (1–1.5 μM) removed the hyperpolarization mediated by GABAB-GirK stimulation (Figures 9A,E; 5.9 ± 2.7%; n = 3, Figures 9B,E; 4.2 ± 2.4%, n = 4), while this effect was not evident at 0.5 μM (Figures 9C,E; −7.2 ± 4.8% n = 4). In fact, the hyperpolarization could be eliminated when the cocktail was washed (Figure 9C). Finally, Aβ-induced depolarization was mimicked by tertiapin-Q, the specific antagonist of GirK channels (Figures 9D,E; 5.5 ± 1.5%; n = 4), indicating that Aβ25–35 directly affects GirK channels conductance.

Bottom Line: Aβ perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP.Aβ action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease.In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all Aβ effects previously described.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Neurofisiología y Comportamiento, Facultad de Medicina de Ciudad Real, Universidad de Castilla-La Mancha Ciudad Real, Spain ; Department of Fisiología y Farmacología, Universidad de Salamanca Salamanca, Spain.

ABSTRACT
Last evidences suggest that, in Alzheimer's disease (AD) early stage, Amyloid-β (Aβ) peptide induces an imbalance between excitatory and inhibitory neurotransmission systems resulting in the functional impairment of neural networks. Such alterations are particularly important in the septohippocampal system where learning and memory processes take place depending on accurate oscillatory activity tuned at fimbria-CA3 synapse. Here, the acute effects of Aβ on CA3 pyramidal neurons and their synaptic activation from septal part of the fimbria were studied in rats. A triphasic postsynaptic response defined by an excitatory potential (EPSP) followed by both early and late inhibitory potentials (IPSP) was evoked. The EPSP was glutamatergic acting on ionotropic receptors. The early IPSP was blocked by GABAA antagonists whereas the late IPSP was removed by GABAB antagonists. Aβ perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP. Aβ action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease. In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all Aβ effects previously described. Thus, our findings suggest that Aβ altering GirK channels conductance in CA3 pyramidal neurons might have a key role in the septohippocampal activity dysfunction observed in AD.

No MeSH data available.


Related in: MedlinePlus