Cargando…

Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment in...

Descripción completa

Detalles Bibliográficos
Autores principales: Song, Lingzhen, Xu, Xiaxia, Putthoff, Peggy, Fleck, David, Spehr, Marc, Hanganu-Opatz, Ileana L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805616/
https://www.ncbi.nlm.nih.gov/pubmed/34844990
http://dx.doi.org/10.1523/JNEUROSCI.1203-21.2021
_version_ 1784643272762720256
author Song, Lingzhen
Xu, Xiaxia
Putthoff, Peggy
Fleck, David
Spehr, Marc
Hanganu-Opatz, Ileana L.
author_facet Song, Lingzhen
Xu, Xiaxia
Putthoff, Peggy
Fleck, David
Spehr, Marc
Hanganu-Opatz, Ileana L.
author_sort Song, Lingzhen
collection PubMed
description Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development. SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.
format Online
Article
Text
id pubmed-8805616
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Society for Neuroscience
record_format MEDLINE/PubMed
spelling pubmed-88056162022-02-02 Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction Song, Lingzhen Xu, Xiaxia Putthoff, Peggy Fleck, David Spehr, Marc Hanganu-Opatz, Ileana L. J Neurosci Research Articles Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development. SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders. Society for Neuroscience 2022-01-26 /pmc/articles/PMC8805616/ /pubmed/34844990 http://dx.doi.org/10.1523/JNEUROSCI.1203-21.2021 Text en Copyright © 2022 Song et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Articles
Song, Lingzhen
Xu, Xiaxia
Putthoff, Peggy
Fleck, David
Spehr, Marc
Hanganu-Opatz, Ileana L.
Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
title Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
title_full Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
title_fullStr Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
title_full_unstemmed Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
title_short Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
title_sort sparser and less efficient hippocampal-prefrontal projections account for developmental network dysfunction in a model of psychiatric risk mediated by gene-environment interaction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805616/
https://www.ncbi.nlm.nih.gov/pubmed/34844990
http://dx.doi.org/10.1523/JNEUROSCI.1203-21.2021
work_keys_str_mv AT songlingzhen sparserandlessefficienthippocampalprefrontalprojectionsaccountfordevelopmentalnetworkdysfunctioninamodelofpsychiatricriskmediatedbygeneenvironmentinteraction
AT xuxiaxia sparserandlessefficienthippocampalprefrontalprojectionsaccountfordevelopmentalnetworkdysfunctioninamodelofpsychiatricriskmediatedbygeneenvironmentinteraction
AT putthoffpeggy sparserandlessefficienthippocampalprefrontalprojectionsaccountfordevelopmentalnetworkdysfunctioninamodelofpsychiatricriskmediatedbygeneenvironmentinteraction
AT fleckdavid sparserandlessefficienthippocampalprefrontalprojectionsaccountfordevelopmentalnetworkdysfunctioninamodelofpsychiatricriskmediatedbygeneenvironmentinteraction
AT spehrmarc sparserandlessefficienthippocampalprefrontalprojectionsaccountfordevelopmentalnetworkdysfunctioninamodelofpsychiatricriskmediatedbygeneenvironmentinteraction
AT hanganuopatzileanal sparserandlessefficienthippocampalprefrontalprojectionsaccountfordevelopmentalnetworkdysfunctioninamodelofpsychiatricriskmediatedbygeneenvironmentinteraction