The number of striatal cholinergic interneurons expressing calretinin is increased in parkinsonian monkeys

The most abundant interneurons in the primate striatum are those expressing the calcium-binding protein calretinin (CR). The present immunohistochemical study provides detailed assessments of their morphological traits, number, and topographical distribution in normal monkeys (Macaca fascicularis) and in monkeys rendered parkinsonian (PD) by MPTP intoxication. In primates, the CR + striatal interneurons comprise small (8-12 mu m), medium (12-20 mu m) and large-sized (20-45 mu m) neurons, each with distinctive morphologies. The small CR + neurons were 2-3 times more abundant than the medium-sized CR + neurons, which were 20-40 times more numerous than the large CR + neurons. In normal and PD monkeys, the density of small and medium-sized CR + neurons was twice as high in the caudate nucleus than in the putamen, whereas the inverse occurred for the large CR + neurons. Double immunostaining experiments revealed that only the large-sized CR + neurons expressed choline acetyltransferase (ChAT). The number of large CR + neurons was found to increase markedly (4-12 times) along the entire anteroposterior extent of both the caudate nucleus and putamen of PD monkeys compared to controls. Comparison of the number of large CR-/ChAT + and CR +/ChAT + neurons together with experiments involving the use of bromo-deoxyuridine (BrdU) as a marker of newly generated cells showed that it is the expression of CR by the large ChAT + striatal interneurons, and not their absolute number, that is increased in the dopamine-depleted striatum. These findings reveal the modulatory role of dopamine in the phenotypic expression of the large cholinergic striatal neurons, which are known to play a crucial role in PD pathophysiology. (C) 2016 Elsevier Inc. All rights reserved.