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Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment

72 Pages Posted: 17 Apr 2019 Sneak Peek Status: Under Review

See all articles by Mattia Chini

Mattia Chini

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Jastyn A. Pöpplau

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Christoph Lindemann

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Laura Carol-Perdiguer

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Marilena Hnida

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Victoria Oberländer

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Xiaxia Xu

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Joachim Ahlbeck

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Sebastian H. Bitzenhofer

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Christoph Mulert

University Medical Center Hamburg-Eppendorf - Psychiatry Neuroimaging Branch (PNB)

Ileana Hanganu-Opatz

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

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Abstract

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here we address this open question combining in vivo electrophysiology, optogenetics, neuroanatomy and behavioral assays during development in mice mimicking the dual genetic – environmental etiology of psychiatric disorders. We report that pyramidal neurons in layer II/III of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Transient administration of minocycline, potentially acting via microglial cells, rescues morphological, synaptic and functional neuronal deficits, and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.

Suggested Citation

Chini, Mattia and Pöpplau, Jastyn A. and Lindemann, Christoph and Carol-Perdiguer, Laura and Hnida, Marilena and Oberländer, Victoria and Xu, Xiaxia and Ahlbeck, Joachim and Bitzenhofer, Sebastian H. and Mulert, Christoph and Hanganu-Opatz, Ileana, Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment (April 15, 2019). Available at SSRN: https://ssrn.com/abstract=3372974 or http://dx.doi.org/10.2139/ssrn.3372974
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mattia Chini

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Jastyn A. Pöpplau

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Christoph Lindemann

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Laura Carol-Perdiguer

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Marilena Hnida

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Victoria Oberländer

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Xiaxia Xu

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Joachim Ahlbeck

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Sebastian H. Bitzenhofer

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology

Germany

Christoph Mulert

University Medical Center Hamburg-Eppendorf - Psychiatry Neuroimaging Branch (PNB)

Germany

Ileana Hanganu-Opatz (Contact Author)

University Medical Center Hamburg-Eppendorf - Developmental Neurophysiology ( email )

Germany

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