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Cited by 90Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchNeuroscience and Neuropharmacology Research

Toward a glutamate hypothesis of frontotemporal dementia

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Benussi, Alberto, Alberici, Antonella, Buratti, Emanuele, Ghidoni, Roberta, Gardoni, Fabrizio, Di Luca, Monica, Padovani, Alessandro, Borroni, Barbara·2019·Frontiers in Neuroscience
DOI 10.3389/fnins.2019.00304PMC PMC6449454
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Abstract

Frontotemporal dementia (FTD) is a heterogenous neurodegenerative disorder characterized by the accumulation of Tau and TDP-43 inclusions. Emerging evidence has shown that FTD is characterized by a series of changes in several neurotransmitter systems, including serotonin, dopamine, GABA and, above all, glutamate. Indeed, several studies have now provided preclinical and clinical evidence that glutamate is key in the pathogenesis of FTD. Animal models of FTD have shown a selective hypofunction in NMDA and AMPA receptors, while in patients, glutamatergic pyramidal neurons are depleted in several areas, including the frontal and temporal cortices. Recently, a selective involvement of the AMPA GluA3 subunit has been observed in patients with autoimmune anti-GluA3 antibodies, which accounted for nearly 25% of FTD patients, leading to a decrease of the GluA3 subunit synaptic localization of the AMPA receptor and loss of dendritic spines. Other in vivo evidence of the involvement of the glutamatergic system in FTD derives from non-invasive brain stimulation studies using transcranial magnetic stimulation, in which specific stimulation protocols have indirectly identified a selective and prominent impairment in glutamatergic circuits in patients with both sporadic and genetic FTD. In view of limited disease modifying therapies to slow or revert disease progression in FTD, an important approach could consist in targeting the neurotransmitter deficits, similarly to what has been achieved in Parkinson’s disease with dopaminergic therapy or Alzheimer’s disease with cholinergic therapy. In this review, we summarize the current evidence concerning the involvement of the glutamatergic system in FTD, suggesting the development of new therapeutic strategies.

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  • FTD-tau is associated with glutamatergic neuronal loss in frontal and temporal cortices.

    “FTD-tau is associated with glutamatergic neuronal loss in frontal and temporal cortices (Benussi et al., 2019).”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Benussi et al., 2019

    The Abstract reports depletion of glutamatergic pyramidal neurons in the frontal and temporal cortices of patients with FTD. It does not specify that this finding applies to FTD-tau; the Introduction identifies tau as one of several FTD pathologies. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Benussi, A., Alberici, A., Buratti, E., Ghidoni, R., Gardoni, F., Di Luca, M., Padovani, A., & Borroni, B.
Affiliations
  • University of Brescia (IT)
  • International Centre for Genetic Engineering and Biotechnology (IT)
  • Centro San Giovanni di Dio Fatebenefratelli (IT)
  • University of Milan (IT)
Corresponding author
Borroni, Barbara
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2019-03-29
Volume
13
Pages
304-304
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2019.00304
PMC
PMC6449454
OpenAlex
W2928352487
Cited by
90
References
99
Citations by year
2026: 12 · 2025: 9 · 2024: 2 · 2023: 13 · 2022: 19 · 2021: 16 · 2020: 15 · 2019: 3 · 2018: 1
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
Funders
Ministero della Salute
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
frontotemporal dementia, glutamate, glutamatergic system, NMDA receptor, AMPA receptors, dendritic spines, transcranial magnetic stimulation, neurotransmitter deficits, disease-modifying therapy

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