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T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS
BACKGROUND: Aberrant activity of microglia, the primary innate immune cells of the brain parenchyma, may play a role in the etiology and pathophysiology of schizophrenia and related disorders. While current immunopsychiatric research indicates that microglial hyperactivity may contribute to psychoti...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234605/ http://dx.doi.org/10.1093/schbul/sbaa029.739 |
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author | Schalbetter, Sina-Maria Dawson, Kara Müller, Flavia Scarborough, Joseph Weber-Stadlbauer, Ulrike Ivanov, Andranik Mattei, Daniele Richetto, Juliet Notter, Tina Meyer, Urs |
author_facet | Schalbetter, Sina-Maria Dawson, Kara Müller, Flavia Scarborough, Joseph Weber-Stadlbauer, Ulrike Ivanov, Andranik Mattei, Daniele Richetto, Juliet Notter, Tina Meyer, Urs |
author_sort | Schalbetter, Sina-Maria |
collection | PubMed |
description | BACKGROUND: Aberrant activity of microglia, the primary innate immune cells of the brain parenchyma, may play a role in the etiology and pathophysiology of schizophrenia and related disorders. While current immunopsychiatric research indicates that microglial hyperactivity may contribute to psychotic illness in some cases, the diametrical opposite (i.e. microglial hypoactivity) may be pathologically and therapeutically relevant for others. The latter hypothesis, however, remains largely unexplored and thus warrants investigation. METHODS: We aimed at developing a model system in mice, in which the short- and long-term effects of selective, temporary and local depletion of microglia can be studied experimentally. This model system is based on intracerebral injection of clodronate disodium salt (CDS) into selected brain areas of interest. The behavioral and cognitive effects of temporary microglia depletion in the adolescent medial frontal cortex (mPFC) were assessed after full microglia recovery in adulthood. In addition, genome-wide transcriptional profiling was conducted during the peak of microglia depletion and after full microglia recovery in the mPFC. RESULTS: We show that a single intracerebral injection of CDS is a suitable and efficient approach to selectively deplete microglia without affecting astrocytes and neurons in-vivo, leading to a robust (~ 80% depletion) but temporary (~ 1 week) microglia deficiency in selected brain areas of interest. Using this model, we further demonstrate that CDS injection into mPFC during late adolescence (6 weeks of age) causes numerous mPFC-related cognitive dysfunctions in adulthood, that is, when microglial cells have been fully restored again. The spectrum of cognitive deficits included impairments in social recognition memory, temporal order memory and extinction of conditioned fear responses. These deficits emerged similarly in male and female animals and were paralleled by a permanent transcriptional dysregulation of genes relevant for synaptic refinement and stability. Intriguingly, CDS injections into the mPFC during early adolescence (4 weeks of age) or adulthood (12 weeks of age) did not induce similar cognitive dysfunctions in adulthood. DISCUSSION: Taken together, the present data demonstrate that temporary prefrontal microglia deficiency during adolescence leads to permanent cognitive impairments in adulthood. Our findings further highlight that distinct adolescent stages of cortical maturation show a differing sensitivity towards the long-term cognitive effects of temporary microglia hypoactivity. |
format | Online Article Text |
id | pubmed-7234605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72346052020-05-23 T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS Schalbetter, Sina-Maria Dawson, Kara Müller, Flavia Scarborough, Joseph Weber-Stadlbauer, Ulrike Ivanov, Andranik Mattei, Daniele Richetto, Juliet Notter, Tina Meyer, Urs Schizophr Bull Poster Session III BACKGROUND: Aberrant activity of microglia, the primary innate immune cells of the brain parenchyma, may play a role in the etiology and pathophysiology of schizophrenia and related disorders. While current immunopsychiatric research indicates that microglial hyperactivity may contribute to psychotic illness in some cases, the diametrical opposite (i.e. microglial hypoactivity) may be pathologically and therapeutically relevant for others. The latter hypothesis, however, remains largely unexplored and thus warrants investigation. METHODS: We aimed at developing a model system in mice, in which the short- and long-term effects of selective, temporary and local depletion of microglia can be studied experimentally. This model system is based on intracerebral injection of clodronate disodium salt (CDS) into selected brain areas of interest. The behavioral and cognitive effects of temporary microglia depletion in the adolescent medial frontal cortex (mPFC) were assessed after full microglia recovery in adulthood. In addition, genome-wide transcriptional profiling was conducted during the peak of microglia depletion and after full microglia recovery in the mPFC. RESULTS: We show that a single intracerebral injection of CDS is a suitable and efficient approach to selectively deplete microglia without affecting astrocytes and neurons in-vivo, leading to a robust (~ 80% depletion) but temporary (~ 1 week) microglia deficiency in selected brain areas of interest. Using this model, we further demonstrate that CDS injection into mPFC during late adolescence (6 weeks of age) causes numerous mPFC-related cognitive dysfunctions in adulthood, that is, when microglial cells have been fully restored again. The spectrum of cognitive deficits included impairments in social recognition memory, temporal order memory and extinction of conditioned fear responses. These deficits emerged similarly in male and female animals and were paralleled by a permanent transcriptional dysregulation of genes relevant for synaptic refinement and stability. Intriguingly, CDS injections into the mPFC during early adolescence (4 weeks of age) or adulthood (12 weeks of age) did not induce similar cognitive dysfunctions in adulthood. DISCUSSION: Taken together, the present data demonstrate that temporary prefrontal microglia deficiency during adolescence leads to permanent cognitive impairments in adulthood. Our findings further highlight that distinct adolescent stages of cortical maturation show a differing sensitivity towards the long-term cognitive effects of temporary microglia hypoactivity. Oxford University Press 2020-05 2020-05-18 /pmc/articles/PMC7234605/ http://dx.doi.org/10.1093/schbul/sbaa029.739 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Poster Session III Schalbetter, Sina-Maria Dawson, Kara Müller, Flavia Scarborough, Joseph Weber-Stadlbauer, Ulrike Ivanov, Andranik Mattei, Daniele Richetto, Juliet Notter, Tina Meyer, Urs T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS |
title | T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS |
title_full | T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS |
title_fullStr | T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS |
title_full_unstemmed | T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS |
title_short | T179. WHEN TOO LITTLE IS TOO MUCH: TEMPORARY PREFRONTAL MICROGLIA DEFICIENCY DURING ADOLESCENCE IMPAIRS ADULT BRAIN FUNCTIONS |
title_sort | t179. when too little is too much: temporary prefrontal microglia deficiency during adolescence impairs adult brain functions |
topic | Poster Session III |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234605/ http://dx.doi.org/10.1093/schbul/sbaa029.739 |
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