PT  - JOURNAL ARTICLE
AU  - Mattia Chini
AU  - Christoph Lindemann
AU  - Jastyn A. Pöpplau
AU  - Xiaxia Xu
AU  - Joachim Ahlbeck
AU  - Sebastian H. Bitzenhofer
AU  - Christoph Mulert
AU  - Ileana L. Hanganu-Opatz
TI  - Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness
AID  - 10.1101/254656
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 254656
4099  - http://biorxiv.org/content/early/2018/01/27/254656.short
4100  - http://biorxiv.org/content/early/2018/01/27/254656.full
AB  - Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal-hippocampal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Combining in vivo electrophysiology and optogenetics with neuroanatomy and pharmacology in neonatal mice mimicking the dual genetic - environmental etiology of psychiatric disorders, we identified pyramidal neurons in layer II/III of the prefrontal cortex as key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing result from sparser dendritic arborization and lower spine density. Pharmacological modulation of aberrantly hyper-mature microglia rescues morphological, synaptic and functional neuronal deficits and restores the early circuit function. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.HighlightsMice mimicking the etiology of mental illness have dysregulated prefrontal networkStructural and synaptic deficits cause abnormal rate and timing of pyramidal firingWeaker activation of prefrontal circuits results from deficits of pyramidal neuronsRescue of microglial function restores developing prefrontal circuits