Abstract
Mutations in the Integral membrane protein 2B (ITM2b/BRI2) gene, which codes for a protein called BRI2, cause familial British and Danish dementia (FBD and FDD). Loss of BRI2 function and/or accumulation of amyloidogenic mutant BRI2-derived peptides have been proposed to mediate FDD and FBD pathogenesis by impairing synaptic Long-term potentiation (LTP). However, the precise site and nature of the synaptic dysfunction remain unknown. Here we use a genetic approach to inactivate Itm2b in either presynaptic (CA3), postsynaptic (CA1) or both (CA3 + CA1) neurons of the hippocampal Schaeffer-collateral pathway in both female and male mice. We show that after CA3 + CA1 Itm2b inactivation, spontaneous glutamate release and AMPAR-mediated responses are decreased, while short-term synaptic facilitation is increased. Moreover, AMPAR-mediated responses are decreased after postsynaptic but not presynaptic deletion of Itm2b. In contrast, the probability of spontaneous glutamate release is decreased, while short-term synaptic facilitation is increased, primarily after presynaptic deletion of Itm2b. Collectively, these results indicate a dual physiological role of Itm2b in the regulation of excitatory synaptic transmission at both presynaptic termini and postsynaptic termini and suggest that presynaptic and postsynaptic dysfunctions may be a pathogenic event leading to dementia and neurodegeneration in FDD and FBD.
Highlights
The conditions known as FDD and FBD are due to autosomal dominant mutations in the ITM2b gene[1,2]
These studies suggest that FDD and FBD may be caused by loss of BRI2 function and increased Aβ-precursor protein (APP) processing and that Long-term potentiation (LTP) deficits caused by the loss of Bri[2] may be a cellular precursor of dementia
Itm2b knock-out (Itm2bKO) and floxed Itm2b (Itm2bf/f) mice were derived as described previously[7]. To generate these animals we targeted Itm2b exon 2 because it encodes for the transmembrane region and the proximal part of the extra cellular region of Bri[2], which is involved in APP interaction[4,8]
Summary
The conditions known as FDD and FBD are due to autosomal dominant mutations in the ITM2b gene[1,2]. Analysis of FDDKI and FBDKI mice, two knock-in mouse models of FDD and FBD that carry one mutant and one wild-type Itm2b allele, has shown that the Danish and British mutations cause the loss of Bri[2] protein, LTP deficits and memory impairments; interestingly, these alterations are APP-dependent[9,10,11,12,13,14,15]. Mice carrying one null Itm2b/Bri[2] have similar deficits[10] These studies suggest that FDD and FBD may be caused by loss of BRI2 function and increased APP processing and that LTP deficits caused by the loss of Bri[2] may be a cellular precursor of dementia. This strategy allows examination of the effects of simultaneous Itm2b inactivation in both presynaptic and postsynaptic neurons as well as selective Itm2b inactivation in either presynaptic or postsynaptic neurons of the Schaeffer-collateral pathway
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