title: The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.
abstract: Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca2+transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Page
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Hamersky
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Gallo
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Rannals
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Calcaterra
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Campbell
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mayfield
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Briley
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Phan
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.|Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Maher
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000196:embryology / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism; D000073940:Transcription Factor 4 / Q000378:metabolism* / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; C491192:Tcf4 protein, rat; D000073940:Transcription Factor 4