sites 136, 154, and 171 are associated with varying susceptibility to ovine scrapie. (These ovine sites correspond to human sites 133, 151, and 168.) Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whereas PrP-ARR is associated with resistance. The National Scrapie Plan of the UK aims to breed out these scrapie polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie, so this may prove unfruitful. Function Nervous system The strong association to neurodegenerative diseases raises many questions of the function of PrP in the brain. A common approach is using PrP-knockout and transgenic mice to investigate deficiencies and differences. Initial attempts produced two strains of PrP-null mice that show no physiological or developmental differences when subjected to an array of tests. However, more recent strains have shown significant cognitive abnormalities. As the null mice age, a marked loss of Purkinje cells in the cerebellum results in decreased motor coordination. However, this effect is not a direct result of PrP's absence, and rather arises from increased Doppel gene expression. Other observed differences include reduced stress response and increased exploration of novel environments. Circadian rhythm is altered in null mice. Fatal familial insomnia is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP's involvement in sleep-wake cycles. In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night. Memory While null mice exhibit normal learning ability and short-term memory, long-term memory consolidation deficits have been demonstrated. As with ataxia, this is attributable to Doppel gene expression. However, spatial learning, a predominantly hippocampal-function, is decreased in the null mice and can be recovered with the reinstatement of PrP in neurons; this indicates that loss of PrP function is the cause. The interaction of hippocampal PrP with laminin (LN) is pivotal in memory processing and is likely modulated by the kinases PKA and ERK1/2. Further support for PrP's role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV. Down syndrome patients with a single valine substitution have been linked to earlier cognitive decline. Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline. All of these studies investigated