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Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments
BACKGROUND: Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are also associated with d...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893396/ https://www.ncbi.nlm.nih.gov/pubmed/24252661 http://dx.doi.org/10.1186/2051-5960-1-34 |
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author | Levenga, Josien Krishnamurthy, Pavan Rajamohamedsait, Hameetha Wong, Helen Franke, Thomas F Cain, Peter Sigurdsson, Einar M Hoeffer, Charles A |
author_facet | Levenga, Josien Krishnamurthy, Pavan Rajamohamedsait, Hameetha Wong, Helen Franke, Thomas F Cain, Peter Sigurdsson, Einar M Hoeffer, Charles A |
author_sort | Levenga, Josien |
collection | PubMed |
description | BACKGROUND: Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs. RESULTS: We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABA(A)R agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice. CONCLUSIONS: We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies. |
format | Online Article Text |
id | pubmed-3893396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-38933962014-01-17 Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments Levenga, Josien Krishnamurthy, Pavan Rajamohamedsait, Hameetha Wong, Helen Franke, Thomas F Cain, Peter Sigurdsson, Einar M Hoeffer, Charles A Acta Neuropathol Commun Research BACKGROUND: Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs. RESULTS: We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABA(A)R agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice. CONCLUSIONS: We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies. BioMed Central 2013-07-11 /pmc/articles/PMC3893396/ /pubmed/24252661 http://dx.doi.org/10.1186/2051-5960-1-34 Text en Copyright © 2013 Levenga et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Levenga, Josien Krishnamurthy, Pavan Rajamohamedsait, Hameetha Wong, Helen Franke, Thomas F Cain, Peter Sigurdsson, Einar M Hoeffer, Charles A Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments |
title | Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments |
title_full | Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments |
title_fullStr | Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments |
title_full_unstemmed | Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments |
title_short | Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments |
title_sort | tau pathology induces loss of gabaergic interneurons leading to altered synaptic plasticity and behavioral impairments |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893396/ https://www.ncbi.nlm.nih.gov/pubmed/24252661 http://dx.doi.org/10.1186/2051-5960-1-34 |
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