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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

Location and electrophysiological characterization of the recorded neurons in hippocampal slices. (A) Experimental design. Diagram of stimulation and recording sites in an hippocampal horizontal section. Schematic location of recording (Rec.) and stimulating (St.) electrodes is shown. Stimuli were applied to the lateral part of the fimbria (shaded area). (B) Response of a CA3 neuron to depolarizing pulses consisted of two to five spikes with marked spike frequency adaptation with a depolarizing current pulse (100 pA, 300 ms) while hyperpolarizing current pulse injection (−160 pA, 300 ms) induced a hyperpolarizing response that allowed us monitoring the input resistance during the experiments. (C) Current-voltage (I-V) relationships for the pyramidal neuron recorded in (B). (D) Reconstruction of the CA3 neuron recorded in (B,C) labeled with biocytin after intracellular recording from 40-μm-thick serial sections. Note the pyramidal morphology of the injected hippocampal cell. ori, stratum oriens; pyr, stratum pyramidale; luc, stratum lucidum; Scale bar 50 μm.
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Figure 1: Location and electrophysiological characterization of the recorded neurons in hippocampal slices. (A) Experimental design. Diagram of stimulation and recording sites in an hippocampal horizontal section. Schematic location of recording (Rec.) and stimulating (St.) electrodes is shown. Stimuli were applied to the lateral part of the fimbria (shaded area). (B) Response of a CA3 neuron to depolarizing pulses consisted of two to five spikes with marked spike frequency adaptation with a depolarizing current pulse (100 pA, 300 ms) while hyperpolarizing current pulse injection (−160 pA, 300 ms) induced a hyperpolarizing response that allowed us monitoring the input resistance during the experiments. (C) Current-voltage (I-V) relationships for the pyramidal neuron recorded in (B). (D) Reconstruction of the CA3 neuron recorded in (B,C) labeled with biocytin after intracellular recording from 40-μm-thick serial sections. Note the pyramidal morphology of the injected hippocampal cell. ori, stratum oriens; pyr, stratum pyramidale; luc, stratum lucidum; Scale bar 50 μm.

Mentions: This study comprises 110 intracellular recordings from pyramidal CA3 neurons (Figure 1), selected on the basis of their RMP (≤ −60 mV) and monosynaptic activation from the fimbria. Recorded neurons did not exhibit action potentials spontaneously at RMP values (−72.5 ± 1.8 mV). The input resistance (Ri) of the neurons was 113.4 ± 6.7 MΩ and the membrane time constant was 77.2 ± 25.4 ms. The direct activation of these neurons by depolarizing current injections (0.1–0.6 nA ; 300 ms) evoked a series of two to five spikes with marked spike frequency adaptation and decreased amplitude and longer duration of the second spike relative to the first one (Figure 1B). The spike amplitude was 101.1 ± 3.2 mV. These characteristics, together with neuronal morphology (Figure 1D) and other electrophysiological properties such as the presence of triphasic afterhyperpolarization (fAHP: 5.6 ± 0.8 mV; mAHP: 10.5 ± 1.5 mV; sAHP: 17.6 ± 1.3 mV) or afterdepolarization (ADP: 3.6 ± 0.5 mV), characterize the principal pyramidal-like neurons widely described in the hippocampus (Spruston and Johnston, 1992; Wittner et al., 2007). The location of selected neurons (n = 10) filled with biocytin is illustrated in Figure 1A. The morphology corresponds to pyramidal neurons in CA3 region of the hippocampus. The cell body is located into the stratum pyramidale and the visible basal dendrites on stratum oriens (Figure 1D).


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)

Location and electrophysiological characterization of the recorded neurons in hippocampal slices. (A) Experimental design. Diagram of stimulation and recording sites in an hippocampal horizontal section. Schematic location of recording (Rec.) and stimulating (St.) electrodes is shown. Stimuli were applied to the lateral part of the fimbria (shaded area). (B) Response of a CA3 neuron to depolarizing pulses consisted of two to five spikes with marked spike frequency adaptation with a depolarizing current pulse (100 pA, 300 ms) while hyperpolarizing current pulse injection (−160 pA, 300 ms) induced a hyperpolarizing response that allowed us monitoring the input resistance during the experiments. (C) Current-voltage (I-V) relationships for the pyramidal neuron recorded in (B). (D) Reconstruction of the CA3 neuron recorded in (B,C) labeled with biocytin after intracellular recording from 40-μm-thick serial sections. Note the pyramidal morphology of the injected hippocampal cell. ori, stratum oriens; pyr, stratum pyramidale; luc, stratum lucidum; Scale bar 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Location and electrophysiological characterization of the recorded neurons in hippocampal slices. (A) Experimental design. Diagram of stimulation and recording sites in an hippocampal horizontal section. Schematic location of recording (Rec.) and stimulating (St.) electrodes is shown. Stimuli were applied to the lateral part of the fimbria (shaded area). (B) Response of a CA3 neuron to depolarizing pulses consisted of two to five spikes with marked spike frequency adaptation with a depolarizing current pulse (100 pA, 300 ms) while hyperpolarizing current pulse injection (−160 pA, 300 ms) induced a hyperpolarizing response that allowed us monitoring the input resistance during the experiments. (C) Current-voltage (I-V) relationships for the pyramidal neuron recorded in (B). (D) Reconstruction of the CA3 neuron recorded in (B,C) labeled with biocytin after intracellular recording from 40-μm-thick serial sections. Note the pyramidal morphology of the injected hippocampal cell. ori, stratum oriens; pyr, stratum pyramidale; luc, stratum lucidum; Scale bar 50 μm.
Mentions: This study comprises 110 intracellular recordings from pyramidal CA3 neurons (Figure 1), selected on the basis of their RMP (≤ −60 mV) and monosynaptic activation from the fimbria. Recorded neurons did not exhibit action potentials spontaneously at RMP values (−72.5 ± 1.8 mV). The input resistance (Ri) of the neurons was 113.4 ± 6.7 MΩ and the membrane time constant was 77.2 ± 25.4 ms. The direct activation of these neurons by depolarizing current injections (0.1–0.6 nA ; 300 ms) evoked a series of two to five spikes with marked spike frequency adaptation and decreased amplitude and longer duration of the second spike relative to the first one (Figure 1B). The spike amplitude was 101.1 ± 3.2 mV. These characteristics, together with neuronal morphology (Figure 1D) and other electrophysiological properties such as the presence of triphasic afterhyperpolarization (fAHP: 5.6 ± 0.8 mV; mAHP: 10.5 ± 1.5 mV; sAHP: 17.6 ± 1.3 mV) or afterdepolarization (ADP: 3.6 ± 0.5 mV), characterize the principal pyramidal-like neurons widely described in the hippocampus (Spruston and Johnston, 1992; Wittner et al., 2007). The location of selected neurons (n = 10) filled with biocytin is illustrated in Figure 1A. The morphology corresponds to pyramidal neurons in CA3 region of the hippocampus. The cell body is located into the stratum pyramidale and the visible basal dendrites on stratum oriens (Figure 1D).

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