Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on?

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Chloride homeostasis, the main determinant factor for the dynamic tuning of GABAergic inhibition during development, has emerged as a key element altered in a wide variety of brain disorders. Accordingly, developmental disorders such as schizophrenia, Autism Spectrum Disorder, Down syndrome, epilepsy, and tuberous sclerosis complex (TSC) have been associated with alterations in the expression of genes codifying for either of the two cotransporters involved in the excitatory-to-inhibitory GABA switch, KCC2 and NKCC1. These alterations can result from environmental insults, including prenatal stress and maternal separation which share, as common molecular denominator, the elevation of pro-inflammatory cytokines. In this review we report and systemize recent research articles indicating that different perinatal environmental perturbations affect the expression of chloride transporters, delaying the developmental switch of GABA signaling, and that inflammatory cytokines, in particular interleukin 1β, may represent a key causal factor for this phenomenon. Based on literature data, we provide therefore a unifying conceptual framework, linking environmental hits with the excitatory-to-inhibitory GABA switch in the context of brain developmental disorders.

Related collections

Most cited references 157

Record: found
Abstract: found
Article: found

What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis

Rachel Loomes, Laura Hull, William Polmear Locke Mandy (2017)

To derive the first systematically calculated estimate of the relative proportion of boys and girls with autism spectrum disorder (ASD) through a meta-analysis of prevalence studies conducted since the introduction of the DSM-IV and the International Classification of Diseases, Tenth Revision.

0 comments Cited 591 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Maternal immune activation: Implications for neuropsychiatric disorders.

Myka Estes, A McAllister (2016)

Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This Review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also discussed. Finally, the need for more research in this nascent field and the implications for identifying and developing new treatments for individuals at heightened risk for neuroimmune disorders are considered.

0 comments Cited 292 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Neuroglial activation and neuroinflammation in the brain of patients with autism.

Diana L Vargas, Caterina Nascimbene, Chitra Krishnan … (2005)

Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.

0 comments Cited 265 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Davide Pozzi:

ORCID: http://orcid.org/0000-0001-6436-0556

davide.pozzi@humanitasresearch.it

Michela Matteoli: michela.matteoli@hunimed.eu

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 15 October 2020

Publication date PMC-release: 15 October 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 349

Affiliations

[1 ]GRID grid.452490.e, Humanitas University, Department of Biomedical Science, ; Via Rita Levi Montalcini 4, Pieve Emanuele, MI Italy

[2 ]GRID grid.417728.f, ISNI 0000 0004 1756 8807, Humanitas Clinical and Research Center — IRCCS, ; via Manzoni 56, Rozzano, MI Italy

[3 ]GRID grid.418879.b, ISNI 0000 0004 1758 9800, CNR Institute of Neuroscience, ; Milan, Italy

Author information

Davide Pozzi http://orcid.org/0000-0001-6436-0556

Article

Publisher ID: 1027

DOI: 10.1038/s41398-020-01027-6

PMC ID: 7562743

PubMed ID: 33060559

SO-VID: 7b0cdd4d-5394-4aa5-97c1-dde9fbea2b30

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 April 2020

Date revision received : 8 September 2020

Date accepted : 14 September 2020

Funding

Funded by: FundRef https://doi.org/10.13039/501100002803, Fondazione Cariplo (Cariplo Foundation);

Award ID: 2017-0886

Award ID: 2019-1973

Award Recipient : Davide Pozzi Irene Corradini

Funded by: FundRef https://doi.org/10.13039/501100002426, Fondazione Telethon (Telethon Foundation);

Award ID: GGP19226A

Award Recipient : Davide Pozzi

Funded by: FundRef https://doi.org/10.13039/501100009882, Regione Lombardia (Region of Lombardy);

Award ID: ID239047

Award Recipient : Michela Matteoli

Funded by: FundRef https://doi.org/10.13039/501100003407, Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research);

Award ID: 2017A9MK4R

Award Recipient : Michela Matteoli