A familial Danish dementia rat shows impaired presynaptic and postsynaptic glutamatergic transmission

Familial British dementia and familial Danish dementia are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both presynaptic and postsynaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of amyloid-beta precursor protein (APP), whose mutations cause familial forms of Alzheimer's disease (AD) (familial AD). To study the pathogenic mechanisms triggered by the Danish mutation, we generated rats carrying the Danish mutation in the rat Itm2b gene (Itm2b(D) rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid beta (A beta), a proteolytic product of APP, to AD, Itm2b(D) rats were engineered to express two humanized App alleles and produce human A beta. Here, we studied young Itm2b(D) rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2b(D) rats not only present subtle changes in human A beta levels along with decreased spontaneous glutamate release and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid receptor-mediated responses but also had increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These alterations in excitatory interneuronal communication can impair learning and memory processes and were akin to those observed in adult mice producing rodent A beta and carrying either the Danish or British mutations in the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses across species and early in life. Future studies will determine whether this phenomenon represents an early pathogenic event in human dementia.

Automated summary

The study of rats carrying the Danish mutation in the Itm2b gene revealed early pathogenic changes related to neuronal communication and synaptic transmission. These alterations may impair learning and memory processes, resembling the observations in mice carrying other related gene mutations.