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Hippocampal synaptic plasticity disruption by amyloid‐β (Aβ) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G‐protein‐gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G‐protein‐coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ1–42. In vitro electrophysiological recordings from slices showed that Aβ1–42 alters synaptic plasticity by switching high‐frequency stimulation (HFS) induced long‐term potentiation (LTP) to long‐term depression (LTD), which led to in vivo hippocampal‐dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS‐induced LTP and habituation memory from Aβ1–42 action. Moreover, when GirK channels were specifically blocked by Tertiapin‐Q, their activation with ML297 failed to rescue LTP from the HFS‐dependent LTD induced by Aβ1–42. On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ1–42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ1–42 to down‐regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aβ‐mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS‐induced LTP into LTD. [ABSTRACT FROM AUTHOR]

Background: In early stages of Alzheimer's disease, disruption of learning and memory processes that rely on hippocampal performance correlates with aberrant patterns of synchronous neuronal activity that arise prior to evident neurodegeneration. These disturbances emerge as a result of neuronal hyperexcitability and synaptic dysfunction induced by soluble forms of amyloid‐β (Aβ) peptide, which trigger an imbalance between excitatory and inhibitory neurotransmission systems. The molecular mechanisms underlying these alterations remain unclear but functional evidence points to alteration of neuronal excitability playing a pivotal role in early Aβ‐induced AD pathogenesis. Although Aβ1‐42 and Aβ1‐40 are widely known for their clinical relevance, Aβ25‐35 has been proposed as the biologically active fragment. In contrast to other Aβ isoforms, Aβ25‐35 does not generate ion‐permeable pores in neuronal membrane, but it has been shown to induce major neuropathological signs related to early AD stages. Hence, it has been extensively used to study the pathophysiological events related to Aβ‐induced neuronal dysfunction. It remains to be explored, however, whether Aβ25‐35 mimics the neurotoxic effects on the hippocampus exhibited by other clinically relevant species such as Aβ1‐42 (Sánchez‐Rodriguez et al., 2017, 2019, 2020). Methods: Here, we systematically characterized the effects of Aβ25‐35 on hippocampal function at different —behavior, networks and synapses— levels of complexity in behaving mice prepared for chronic intracerebroventricular injections. Likewise, animals were implanted with electrodes for in vivo recordings at the hippocampal CA1 area and electrical stimulation of the Schaffer collateral pathway. Results: Our data showed evident learning and memory impairments in hippocampal‐dependent tasks such as novel object recognition and open field habituation tests. Underlying these deficits, local field potential (LFP) recordings revealed an altered oscillatory activity. Additionally, theta and gamma rhythms, crucially involved in successful memory encoding, were abnormally increased. Lastly, we also found impairments in long‐term synaptic plasticity at the CA3‐CA1 synapse, where Aβ25‐35 transformed long‐term potentiation (LTP) into long‐term depression (LTD). Conclusions: Taken together, these results support the notion that Aβ25‐35‐mediated effects on synaptic properties and neural network activity mimicked those exerted by Aβ1‐42. Thus, we verified the potentiality of the Aβ25‐35 peptide to study the hippocampal pathophysiology of early amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Hippocampal synaptic plasticity disruption by amyloid‐β (Aβ) peptides is thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G‐protein‐gated inwardly‐rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G‐protein‐coupled receptors activation. Method: Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ1‐42. In vitro electrophysiological recordings from slices showed that Aβ1‐42 alters synaptic plasticity by switching high frequency stimulation (HFS) induced long‐term potentiation (LTP) to long‐term depression (LTD), which led to in vivo hippocampal‐dependent memory deficits. Result: Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS‐induced LTP and habituation memory from Aβ1‐42 action. Moreover, when GirK channels were specifically blocked by Tertiapin‐Q, their activation with ML297 failed to rescue LTP from the HFS‐dependent LTD induced by Aβ1‐42. On the other hand, the molecular analysis of the recorded slices by western blot showed that expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ1‐42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ1‐42 to downregulate hippocampal GIRK1 subunit expression. Conclusion: Together, our results describe an Aβ‐mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS‐induced LTP into LTD. [ABSTRACT FROM AUTHOR]