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

Tao Yin,Wen Yao,Kelly A Norris,Luciano D’Adamio

doi:10.1016/j.jbc.2021.101089

Abstract

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-β 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 (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid β (Aβ), a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles and produce human Aβ. Here, we studied young Itm2bD rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2bD rats not only present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 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 Aβ 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.

Highlights

We have previously shown that the Danish and British integral membrane protein 2B (ITM2b) mutations lead to reduced glutamatergic neurotransmitter release and αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated responses in adult Itm2bB and Itm2bD mice
To explore early dysfunctions that may underlie initial mechanisms leading to dementia, we studied young knock in (KI) rats
Consistent with the findings in Itm2bD/D mouse KIs [41], we found that Bri2ADan maturation is altered and accumulates in Itm2bD/D primary neurons (Fig. 2)

Summary

Introduction

We have previously shown that the Danish and British ITM2b mutations lead to reduced glutamatergic neurotransmitter release and AMPAR-mediated responses in adult Itm2bB and Itm2bD mice. These reductions are like those seen in adult Itm2b KO mice [41, 46]. MEPSC amplitude and the AMPAR/NMDAR peak current ratio were both decreased in Itm2bD rats, suggesting a postsynaptic reduction of AMPAR-mediated responses These data together with our previously published observations indicate that the synaptic transmission alteration caused by Danish mutation occurs early in life and are neither species nor gene-editing technology specific. These studies underlie the potential relevance of our studies to functional changes caused by the pathogenic ITM2b mutations in human

Results

Discussion

Conclusion