Early hippocampal hyperactivity in a rat model of Alzheimer’s disease
1 Neuronal Networks Group, German Center for Neurodegenerative Diseases (DZNE)
2 Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE)
3 Department of Pharmacology and Therapeutics, Watts Building, Trinity College, Dublin 2, Ireland
4 Light Microscopy Facility, German Center for Neurodegenerative Diseases (DZNE)
5 Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
6 Neuronal Networks Group, German Center for Neurodegenerative Diseases (DZNE), Leibniz Institute for Neurobiology (LIN), Department of Cellular Neuroscience, Magdeburg, Germany
Neuronal network dysfunction is a hallmark of Alzheimer’s disease (AD). However, the underlying pathomechanisms remain elusive. We analyzed the hippocampal micronetwork in a rat model of AD overexpressing hAPP (human amyloid precursor protein) at an early stage of extracellular amyloid beta deposition. We established in-vivo two-photon Ca2+-imaging in the rat hippocampus revealing early neuronal hyperexcitability in APPtg+/+ rats. To determine the influence of altered excitatory transmission on this hyperexcitability, we recorded electrically evoked CA1 EPSPs in freely behaving animals. The synaptic input-output relationships were indistinguishable between 7–9 month-old APPtg-/- and APPtg+/+ rats, challenging the hypothesis of increased glutamatergic synaptic transmission. Surprisingly, also the proximal and distal synaptic inhibition onto CA1 pyramidal cells was unperturbed, arguing against a change of inhibitory transmission as underlying cause of the observed hyperexcitability. However, when we investigated the intrinsic excitability of CA1 pyramidal neurons, we observed an increased neuronal input resistance and a prolonged action potential width. This finding suggests that early-stage neuronal hyperexcitability is mediated by changes in the intrinsic excitability of CA1 pyramidal neurons, rather than by synaptic changes. Thus, our data support the view that altered intrinsic excitability precedes inhibitory and excitatory synaptic dysfunction during disease progression.
This work was supported by COEN, DFG/SFB1089.