In Alzheimer's disease (AD), a decline in explicit memory is one of the earliest signs of disease and is associated with hippocampal dysfunction. Amyloid protein exerts a disruptive impact on neuronal function, but the specific effects on hippocampal network activity are not well known. In this study, fast voltage-sensitive dye imaging and extracellular and whole-cell electrophysiology were used on entorhinal cortical-hippocampal slice preparations to characterize hippocampal network activity in 12–16 month old female APPswe/PSEN1DeltaE9 (APdE9 mice) mice. Aged APdE9 mice exhibited profound disruptions in dentate gyrus circuit activation. High frequency stimulation of the perforant pathway in the dentate gyrus (DG) area of APdE9 mouse tissue evoked abnormally large field potential responses corresponding to the wider neural activation maps. Whole-cell patch clamp recordings of the identified inhibitory interneurons in the molecular layer of DG revealed that they fail to reliably fire action potentials. Taken together, abnormal DG excitability and an inhibitory neuron failure to generate action potentials are suggested to be important contributors to the underlying cellular mechanisms of early-stage Alzheimer's disease pathophysiology.
SUMMARYObjective: Severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome is one of the most devastating childhood epilepsies. Children with SMEI have febrile and afebrile seizures (FS and aFS), ataxia, and social and cognitive dysfunctions. SMEI is pharmacologically intractable and can be fatal in 10-20% of patients. It remains to be elucidated how channelopathies that cause SMEI impact synaptic activities in key neural circuits, and there is an ongoing critical need for alternative methods of controlling seizures in SMEI. Using the SCN1A gene knock-in mouse model of SMEI (mSMEI), we studied hippocampal cell and circuit excitability, particularly during hyperthermia, and tested whether an adenosine A1 receptor (A1R) agonist can reliably control hippocampal circuit hyperexcitability. Methods: Using a combination of electrophysiology (extracellular and whole-cell voltage clamp) and fast voltage-sensitive dye imaging (VSDI), we quantified synaptic excitation and inhibition, spatiotemporal characteristics of neural circuit activity, and hyperthermia-induced febrile seizure-like events (FSLEs) in juvenile mouse hippocampal slices. We used hyperthermia to elicit FSLEs in hippocampal slices, while making use of adenosine A1R agonist N6-cyclopentyladenosine (CPA) to control abnormally widespread neural activity and FSLEs. Results: We discovered a significant excitation/inhibition (E/I) imbalance in mSMEI hippocampi, in which inhibition was decreased and excitation increased. This imbalance was associated with an increased spatial extent of evoked neural circuit activation and a lowered FSLE threshold. We found that a low concentration (50 nM) of CPA blocked FSLEs and reduced the spatial extent of abnormal neural activity spread while preserving basal levels of excitatory synaptic transmission. Significance: Our study reveals significant hippocampal synapse and circuit dysfunctions in mSMEI and demonstrates that the A1R agonist CPA can reliably control hippocampal hyperexcitability and FSLEs in vitro. These findings may warrant further investigations of purinergic agonists as part of the development of new therapeutic approaches for Dravet syndrome.
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