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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

Pharmacological characterization of septohippocampal synaptic response. (A) Recordings from a pyramidal CA3 neuron illustrating a marked reduction of the early IPSP after perfusion with bicuculline (10 μM; specific blocker of GABAA receptors). (B) Blocking of the late IPSP after perfusion with saclofen (200 μM; blocker of GABAB receptor) was accompanied by a mild increase of the early IPSP and EPSP. (C) The increase in the amplitude of EPSP and late IPSP produced by perfusion of bicuculline was reduced by APV application (50 μM; specific blocker of NMDA receptor). Membrane potential was maintained at values more positives than resting membrane potential to assure NMDA receptors functionality. Synaptic response was completely removed with the addition of CNQX (10 μM; competitive non-NMDA receptor antagonist). (D) Blockade of the early IPSP with bicuculline (n = 4) was associated with a marked increase in amplitude of EPSP and late IPSP. Excitatory and inhibitory responses were blocked by CNQX and APV. The cells were held at −75 mV (a membrane potential where NMDA receptor-mediated currents are ). (E) Histograms with relative mean amplitude as percentage of control of the different components of the complex synaptic response (EPSP; early, e.IPSP; and late, l.IPSP) under pharmacological conditions described in (A–D) (**p < 0.001). (F) Both, early and late IPSPs were blocked by bicuculline and saclofen, respectively, while a large repetitive burst of action potential appeared (n = 4). At membrane potential values that assured NMDA activation, this epileptic-like activity could be removed by CNQX. Finally, residual excitatory NMDA response was eliminated by APV perfusion. (G) During the epileptic-like activity induced by both inhibitory components elimination, and at membrane potential values that led NMDA receptor activation, APV perfusion reduced the size of the epileptic response that had to be removed by addition of CNQX (n = 4).
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Figure 3: Pharmacological characterization of septohippocampal synaptic response. (A) Recordings from a pyramidal CA3 neuron illustrating a marked reduction of the early IPSP after perfusion with bicuculline (10 μM; specific blocker of GABAA receptors). (B) Blocking of the late IPSP after perfusion with saclofen (200 μM; blocker of GABAB receptor) was accompanied by a mild increase of the early IPSP and EPSP. (C) The increase in the amplitude of EPSP and late IPSP produced by perfusion of bicuculline was reduced by APV application (50 μM; specific blocker of NMDA receptor). Membrane potential was maintained at values more positives than resting membrane potential to assure NMDA receptors functionality. Synaptic response was completely removed with the addition of CNQX (10 μM; competitive non-NMDA receptor antagonist). (D) Blockade of the early IPSP with bicuculline (n = 4) was associated with a marked increase in amplitude of EPSP and late IPSP. Excitatory and inhibitory responses were blocked by CNQX and APV. The cells were held at −75 mV (a membrane potential where NMDA receptor-mediated currents are ). (E) Histograms with relative mean amplitude as percentage of control of the different components of the complex synaptic response (EPSP; early, e.IPSP; and late, l.IPSP) under pharmacological conditions described in (A–D) (**p < 0.001). (F) Both, early and late IPSPs were blocked by bicuculline and saclofen, respectively, while a large repetitive burst of action potential appeared (n = 4). At membrane potential values that assured NMDA activation, this epileptic-like activity could be removed by CNQX. Finally, residual excitatory NMDA response was eliminated by APV perfusion. (G) During the epileptic-like activity induced by both inhibitory components elimination, and at membrane potential values that led NMDA receptor activation, APV perfusion reduced the size of the epileptic response that had to be removed by addition of CNQX (n = 4).

Mentions: In order to determine the nature of the complex response, a pharmacological dissection of the postsynaptic potential components was performed (Figure 3). The early IPSP was blocked by bicuculline (10 μM, n = 6), a specific blocker of GABAA receptors (Figures 3A,C–E) whereas late IPSP was removed by saclofen (200 μM; n = 5), a specific blocker of GABAB receptors (Figures 3B,E). The excitatory component was increased by early IPSP block with bicuculline (n = 9; Figures 3A,C–E) and presented a glutamatergic nature acting mainly on non-NMDA (n = 5; Figure 3D) receptors, since although its complete elimination required CNQX (10 μM) and APV (50 μM) the cells were held at −75 mV (a membrane potential where NMDA receptor-mediated currents are ). However, when recorded cells were held at more positive values than RMP (n = 4; Figure 3C), NMDA channels were entirely functional and perfusion with APV decreased both bicuculline-enhanced responses, EPSP and late IPSP (Figure 3E), suggesting the participation of NMDA receptors in the response. As previously, complete blockage of EPSP also required CNQX (Figure 3C). In this regard, the pharmacological elimination of glutamatergic responses with CNQX plus APV also abolished the inhibitory response (Figures 3C,D) suggesting that IPSPs were produced by interneurons activation.


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)

Pharmacological characterization of septohippocampal synaptic response. (A) Recordings from a pyramidal CA3 neuron illustrating a marked reduction of the early IPSP after perfusion with bicuculline (10 μM; specific blocker of GABAA receptors). (B) Blocking of the late IPSP after perfusion with saclofen (200 μM; blocker of GABAB receptor) was accompanied by a mild increase of the early IPSP and EPSP. (C) The increase in the amplitude of EPSP and late IPSP produced by perfusion of bicuculline was reduced by APV application (50 μM; specific blocker of NMDA receptor). Membrane potential was maintained at values more positives than resting membrane potential to assure NMDA receptors functionality. Synaptic response was completely removed with the addition of CNQX (10 μM; competitive non-NMDA receptor antagonist). (D) Blockade of the early IPSP with bicuculline (n = 4) was associated with a marked increase in amplitude of EPSP and late IPSP. Excitatory and inhibitory responses were blocked by CNQX and APV. The cells were held at −75 mV (a membrane potential where NMDA receptor-mediated currents are ). (E) Histograms with relative mean amplitude as percentage of control of the different components of the complex synaptic response (EPSP; early, e.IPSP; and late, l.IPSP) under pharmacological conditions described in (A–D) (**p < 0.001). (F) Both, early and late IPSPs were blocked by bicuculline and saclofen, respectively, while a large repetitive burst of action potential appeared (n = 4). At membrane potential values that assured NMDA activation, this epileptic-like activity could be removed by CNQX. Finally, residual excitatory NMDA response was eliminated by APV perfusion. (G) During the epileptic-like activity induced by both inhibitory components elimination, and at membrane potential values that led NMDA receptor activation, APV perfusion reduced the size of the epileptic response that had to be removed by addition of CNQX (n = 4).
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Related In: Results  -  Collection

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Show All Figures
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Figure 3: Pharmacological characterization of septohippocampal synaptic response. (A) Recordings from a pyramidal CA3 neuron illustrating a marked reduction of the early IPSP after perfusion with bicuculline (10 μM; specific blocker of GABAA receptors). (B) Blocking of the late IPSP after perfusion with saclofen (200 μM; blocker of GABAB receptor) was accompanied by a mild increase of the early IPSP and EPSP. (C) The increase in the amplitude of EPSP and late IPSP produced by perfusion of bicuculline was reduced by APV application (50 μM; specific blocker of NMDA receptor). Membrane potential was maintained at values more positives than resting membrane potential to assure NMDA receptors functionality. Synaptic response was completely removed with the addition of CNQX (10 μM; competitive non-NMDA receptor antagonist). (D) Blockade of the early IPSP with bicuculline (n = 4) was associated with a marked increase in amplitude of EPSP and late IPSP. Excitatory and inhibitory responses were blocked by CNQX and APV. The cells were held at −75 mV (a membrane potential where NMDA receptor-mediated currents are ). (E) Histograms with relative mean amplitude as percentage of control of the different components of the complex synaptic response (EPSP; early, e.IPSP; and late, l.IPSP) under pharmacological conditions described in (A–D) (**p < 0.001). (F) Both, early and late IPSPs were blocked by bicuculline and saclofen, respectively, while a large repetitive burst of action potential appeared (n = 4). At membrane potential values that assured NMDA activation, this epileptic-like activity could be removed by CNQX. Finally, residual excitatory NMDA response was eliminated by APV perfusion. (G) During the epileptic-like activity induced by both inhibitory components elimination, and at membrane potential values that led NMDA receptor activation, APV perfusion reduced the size of the epileptic response that had to be removed by addition of CNQX (n = 4).
Mentions: In order to determine the nature of the complex response, a pharmacological dissection of the postsynaptic potential components was performed (Figure 3). The early IPSP was blocked by bicuculline (10 μM, n = 6), a specific blocker of GABAA receptors (Figures 3A,C–E) whereas late IPSP was removed by saclofen (200 μM; n = 5), a specific blocker of GABAB receptors (Figures 3B,E). The excitatory component was increased by early IPSP block with bicuculline (n = 9; Figures 3A,C–E) and presented a glutamatergic nature acting mainly on non-NMDA (n = 5; Figure 3D) receptors, since although its complete elimination required CNQX (10 μM) and APV (50 μM) the cells were held at −75 mV (a membrane potential where NMDA receptor-mediated currents are ). However, when recorded cells were held at more positive values than RMP (n = 4; Figure 3C), NMDA channels were entirely functional and perfusion with APV decreased both bicuculline-enhanced responses, EPSP and late IPSP (Figure 3E), suggesting the participation of NMDA receptors in the response. As previously, complete blockage of EPSP also required CNQX (Figure 3C). In this regard, the pharmacological elimination of glutamatergic responses with CNQX plus APV also abolished the inhibitory response (Figures 3C,D) suggesting that IPSPs were produced by interneurons activation.

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