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

Mattia Chini,Jastyn A Pöpplau,Christoph Lindemann,Laura Carol-Perdiguer,Marilena Hnida,Victoria Oberländer,Xiaxia Xu,Joachim Ahlbeck,Sebastian H Bitzenhofer,Christoph Mulert,Ileana L Hanganu-Opatz

doi:10.1016/j.neuron.2019.09.042

Mattia Chini, Jastyn A Pöpplau + Show 9 more

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https://doi.org/10.1016/j.neuron.2019.09.042

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Journal: Neuron	Publication Date: Nov 13, 2019
Citations: 57	License type: cc-by

Affiliation: University Medical Center Hamburg-Eppendorf

Abstract

SummaryCognitive 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.

Highlights

Cortical function relies on the precise wiring and activation of diverse populations of pyramidal cells and interneurons that are entrained in oscillatory rhythms
We started to elucidate the mechanisms of functional coupling within the developing brain and have shown that pyramidal neurons in the superficial layers of the prefrontal cortex (PFC) play a fundamental role in generating beta/lowgamma oscillations in the neonatal mouse (Bitzenhofer et al, 2017)
We show that pyramidal neurons in superficial layers exhibit major morphological, synaptic, and functional deficits and lack the ability to organize the beta-gamma entrainment of local prelimbic circuits in neonatal dual-hit GE mice, while deep layers neurons are largely unaffected

Summary

Introduction

Cortical function relies on the precise wiring and activation of diverse populations of pyramidal cells and interneurons that are entrained in oscillatory rhythms. Given the uniqueness of the developing brain in its spatial and temporal organization of coordinated activity (Brockmann et al, 2011; Khazipov et al, 2004), the depolarizing action of GABA (Kirmse et al, 2015) and the formation of transient connectivity patterns (Marques-Smith et al, 2016), the functional coupling within immature microcircuits is likely to bear unique traits. We started to elucidate the mechanisms of functional coupling within the developing brain and have shown that pyramidal neurons in the superficial layers of the prefrontal cortex (PFC) play a fundamental role in generating beta/lowgamma oscillations in the neonatal mouse (Bitzenhofer et al, 2017). The circuit dysfunction underlying such abnormalities is still unknown

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