Changes in tyrosine hydroxylase, glutamic acid decar☐ylase and choline acetyltransferase after local microinoculation of scrapie agent into the nigrostriatal system of the golden hamster

Abstract

A microinjection of a homogenate of scrapie agent-infected brain (strain 263 K) into the nigrostriatal system in the golden hamster is followed by the progressive development of the disease which terminates by the death of animals around the 4th month postinoculation. These intracerebral inoculations induce more rapid changes in neuronal activity which can be revealed by the assessment of the specific synthesizing enzymes of neurotransmitter systems. The microinoculation of a homogenate of an infected brain unilaterally into the substantia nigra (SN) provokes a decrease in tyrosine hydroxylase (TH), the synthesizing enzyme for dopamine in the dopaminergic neurones, in the striatum ipsilateral to the injected SN. This biochemical response, specifically induced by the active pathogen, is detectable as soon as the 5th day postinoculation and is detectable towards the 80th day. A return of TH levels to control values is detected after this period. At the end of the incubation period and towards the death of the animals, TH is not different from control TH measured from intact animals. The decrease in TH is concomitant with an increase in striatal glutamic acid decar☐ylase (GAD), the synthesizing enzyme for γ-aminobutyric acid (GABA), measured 20 days postinoculation with no change in choline acetyltransferase (ChAT), the synthesizing enzyme for acetylcholine. Studies of the biochemical responses associated locally to the scrapie agent inoculation have been performed at the striatal level. The intrastriatal administration of the infective agent induces 20 days postinoculation an increase in GAD with no change in TH and ChAT. Ninety days postinoculation, a decrease in GAD was detected associated with an increase in TH with no change in ChAT. The decrease in striatal TH 5 days after inoculation of the scrapie agent in the ipsilateral SN represents in the hamster an early marker of the slow progressive pathologic process which can only be revealed about 80 days postinoculation. The influence of the pathogen in the nigrostriatal system could be specific for certain categories of neurones. The cholinergic neurones are apparently not affected. The dopaminergic neurones seem not to be permanently damaged, as seen by the return of TH to control values during the development of the disease. The GABAergic neurones could represent a preferential target for the pathogen as shown by the early GAD activation and tardive decrease activity.