Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down's syndrome

Mice with segmental trisomy of chromosome 16 (Ts65Dn) have been used as a m odel for Down's syndrome, These mice are born with a normal density of basa l forebrain cholinergic neurons but, like patients with Down's syndrome, un dergo a significant deterioration of these neurons later in life. The time course for this degeneration of cholinergic neurons has not been studied, n or is it known if it correlates with the progressive memory and learning de ficits described. Ts65Dn mice that were 4, 6, 8, and 10 months old were sac rificed for evaluation of basal forebrain morphology, Separate groups of mi ce were tested on visual or spatial discrimination learning and reversal, W e found no alterations in cholinergic markers in 4-month-old Ts65Dn mice, b ut thereafter a progressive decline in density of cholinergic neurons, as w eb as significant shrinkage of cell body size, was seen. A parallel loss of staining for the high-affinity nerve growth factor receptor, trkA, was obs erved at all time points, suggesting a biological mechanism for the cell. l oss involving this growth factor. Other than transient difficulty in learni ng the task requirements, there was no impairment of trisomic mice on visua l discrimination learning and reversal, whereas spatial learning and revers al showed significant deficits, particularly in the mice over 6 months of a ge. Thus, the loss of ChAT-immunoreactive neurons in the basal forebrain wa s coupled with simultaneous deficits in behavioral flexibility on a spatial task occurring for the first time around 6 months of age. These findings s uggest that the loss of cholinergic function and the simultaneous decrease in trkA immunoreactivity in basal forebrain may directly correlate with cog nitive impairment in the Ts65Dn mouse. (C) 2000 Academic Press.