AMPA/KA receptor independent epileptiform bursts in the hippocampus of a mouse model of variant CJD Stéphanie Ratté, John Collinge & J.G.R. Jefferys. Dept. Neuroscience (Neurophysiology), Medical School, University of Birmingham, Edgbaston, B15 2TT (SR, JJ); MRC Prion Unit and Dept Neurodegenerative Disease, Inst Neurology, UCL, Queen Square, London, WC1N 3BG (JC).

Print abstract Search PubMed for: Ratte S Collinge J Jefferys JG

Variant Creutzfeldt-Jakob Disease (vCJD) is a fatal human prion disease linked to the recent BSE epidemic in the UK (Collinge et al., 1996; Bruce et al., 1997; Hill et al., 1997). It differs in clinical features and duration of illness from the more common sporadic CJD (sCJD) (Collinge, 1997; Spencer et al., 2002). We tested the hypothesis that the different symptoms are associated with distinct pathophysiologies at the neuronal and/or local network levels.

Transgenic mice that express normal human prion protein instead of murine prion protein (Tg(HuPrP+/+, Prnp0/0)-152) (Hill et al., 1997) were inoculated intracerebrally with either phosphate buffered saline or brain homogenate from: a patient who died of vCJD, or a patient who died of sCJD, or a control post-mortem case. Mice were killed various times later by cervical dislocation under halothane anaesthesia (Colling et al., 1996). The brain was dissected and 400µm slices were cut and maintained at 32°C in an interface chamber. We recorded intracellular and extracellular responses evoked in CA1 by a bipolar stimulating electrode on the Schaffer collaterals.

In this vCJD model incubation time to symptoms and death is very variable. Only 49% of inoculated mice succumb to the disease, most reaching old age before displaying clinical symptoms. We examined 29 vCJD-prion-infected mice, 148 to 720 days after inoculation. All but one of the mice lacked symptoms, suggesting they were at early stages of the disease. Four of 28 asymptomatic mice and one symptomatic mouse had long all-or-none bursts (up to 1.7 s, mean of 736 ± 150 (s.e.m) ms in 5 slices) in response to pairs of stimuli at 100-500 ms. Such abnormalities were absent from all 36 controls, taken 37 to 716 days after inoculation, and 29 sCJD-prion-infected animals taken 196 to 316 days after inoculation (Fisher's Exact Test p<0.005). A pronounced extracellular negativity in stratum oriens during the burst implicated excitatory synaptic input on pyramidal neuron basal dendrites. The NMDA-receptor antagonist D-APV (25 µM) reversibly blocked these bursts (n=4). Surprisingly, blocking AMPA/KA receptors had no effect on the bursts; they persisted in the presence of CNQX (20µM) or NBQX (20 to 75 µM).

Hence, the vCJD prion strain results in markedly early and unique hippocampal pathophysiology. The NMDA-dependent epileptiform activity does not require AMPA/KA-mediated depolarisation, and the bursts are present only on the second of a pair of pulses, suggesting that paired-pulse dependent mechanisms for NMDA potentiation might be present. Early diagnosis of vCJD remains challenging and these results suggest novel diagnostic approaches as well as drug targets for the treatment of this disease.

Supported by the MRC

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