SEVERE, EARLY AND SELECTIVE LOSS OF A SUBPOPULATION OF GABAERGIC INHIBITORY NEURONS IN EXPERIMENTAL TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

Little is known about the pathogenetic basis of characteristic symptom s in transmissible spongiform encephalopathies (TSEs) such as myoclonu s and characteristic EEG hyperactivity, We investigated the GABAergic system and its subpopulations in mice inoculated with experimental scr apie (ME7, RML, 22A strains) and Creutzfeldt-Jakob disease (CJD; Fujis aki strain), to study damage to inhibitory neurons. Since recent studi es have shown electrophysiological changes in prion protein (PrP) knoc kout mice, we also studied mice lacking or overexpressing the PrP gene . Antibodies against glutamic acid decarboxylase (GAD), parvalbumin (P V), calbindin (CB), and calretinin (CR) were used to stain GABAergic n eurons, and isolectin-B-4 to stain perineuronal nets around PV+ neuron s. In scrapie infected mice, cortical PV+ neurons were severely reduce d while CB+ and CR+ neurons were well preserved. In CJD inoculated mic e, loss of PV+ neurons was severe and occurred very early after inocul ation, PrP-/- and tg20 mice showed normal appearance of PV, CB, CR, GA D+ neurons and their neuropil, and of isolectin-B-4+ perineuronal nets . The early, severe and selective loss of cortical PV+ neurons in expe rimental scrapie and CJD suggest selective loss of PV+ GABAergic neuro ns as important event during disease development, possibly as one basi s of excitatory symptoms in TSEs.