The Familial dementia gene ITM2b/BRI2 facilitates glutamate transmission via both presynaptic and postsynaptic mechanisms

Wen Yao, Tao Yin, Marc D. Tambini, Luciano D’Adamio

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number4862
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Dementia
Glutamic Acid
Long-Term Potentiation
Synaptic Transmission
Genes
Membrane Proteins
Neurons
Peptides
Mutation
Proteins
Familial Danish dementia
Familial British Dementia

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "The Familial dementia gene ITM2b/BRI2 facilitates glutamate transmission via both presynaptic and postsynaptic mechanisms",
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.",
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The Familial dementia gene ITM2b/BRI2 facilitates glutamate transmission via both presynaptic and postsynaptic mechanisms. / Yao, Wen; Yin, Tao; Tambini, Marc D.; D’Adamio, Luciano.

In: Scientific reports, Vol. 9, No. 1, 4862, 01.12.2019.

Research output: Contribution to journalArticle

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