[en] Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges 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 by 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 superficial layers 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. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Chini, Mattia ; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Pöpplau, Jastyn A; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Lindemann, Christoph; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Carol-Perdiguer, Laura; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Hnida, Marilena; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Oberländer, Victoria; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Xu, Xiaxia; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Ahlbeck, Joachim; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Bitzenhofer, Sebastian H; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Mulert, Christoph; Psychiatry Neuroimaging Branch (PNB), Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Hanganu-Opatz, Ileana L; Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: hangop@zmnh.uni-hamburg.de
Language :
English
Title :
Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment.
DFG - Deutsche Forschungsgemeinschaft ERC - European Research Council
Funding text :
We thank Dr. Joseph Gogos for providing the DISC1 mice, Drs. S. Wiegert and T. Oertner for providing opsin derivates, and A. Marquardt, A. Dahlmann, I. Ohmert, and K. Titze for excellent technical assistance. This work was funded by grants from the European Research Council (ERC-2015-CoG 681577 to I.L.H.-O.) and the German Research Foundation (Ha4466/10-1, Ha4466/11-1, Ha4466/12-1, SPP 1665, and SFB 936 B5 to I.L.H.-O. and C6 to C.M.). I.L.H.-O. is a founding member of the FENS Kavli Network of Excellence. I.L.H.-O. conceived the study. M.C. and I.L.H.-O. designed the experiments. M.C. J.A.P. C.L. L.C.-P. M.H. V.O. J.A. and S.H.B. carried out experiments. M.C. and X.X. analyzed the data. M.C. C.M. and I.L.H.-O. interpreted the data. M.C. and I.L.H.-O. wrote the article. All authors discussed and commented on the manuscript. The authors declare no competing interests.We thank Dr. Joseph Gogos for providing the DISC1 mice, Drs. S. Wiegert and T. Oertner for providing opsin derivates, and A. Marquardt, A. Dahlmann, I. Ohmert, and K. Titze for excellent technical assistance. This work was funded by grants from the European Research Council ( ERC-2015-CoG 681577 to I.L.H.-O.) and the German Research Foundation ( Ha4466/10-1 , Ha4466/11-1 , Ha4466/12-1 , SPP 1665 , and SFB 936 B5 to I.L.H.-O. and C6 to C.M.). I.L.H.-O. is a founding member of the FENS Kavli Network of Excellence.
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