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

• Published in: Neuron (Cambridge, Mass.) Vol. 105; no. 1; pp. 60 - 74.e7
• Main Authors: Chini, Mattia, Pöpplau, Jastyn A., Lindemann, Christoph, Carol-Perdiguer, Laura, Hnida, Marilena, Oberländer, Victoria, Xu, Xiaxia, Ahlbeck, Joachim, Bitzenhofer, Sebastian H., Mulert, Christoph, Hanganu-Opatz, Ileana L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.01.2020; Elsevier Limited; Cell Press
• Subjects: Age; Anatomy; Animals; Animals, Newborn; Antibiotics; Atrophy - pathology; Behavior, Animal - physiology; Beta Rhythm - physiology; beta-gamma oscillations; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; Cognitive Dysfunction - physiopathology; Cognitive Dysfunction - prevention & control; Dendrites - pathology; Dendritic branching; Dendritic spines; Dendritic Spines - pathology; development; Electrophysiology; Entrainment; Etiology; Female; Firing rate; Gamma Rhythm - physiology; Genetics; Information processing; Investigations; in vivo electrophysiology; in vivo optogenetics; Male; Mental disorders; Mice; microglia; Microglia - physiology; Microglial cells; Mimicry; Minocycline; Minocycline - pharmacology; Mutation; Nerve Tissue Proteins - genetics; Neural Pathways - physiopathology; Optics; Optogenetics; Poly I-C; Prefrontal cortex; Prefrontal Cortex - pathology; Prefrontal Cortex - physiology; Pyramidal cells; Pyramidal Cells - physiology; pyramidal neurons; recognition memory; development; beta-gamma oscillations; prefrontal cortex; minocycline; pyramidal neurons; in vivo optogenetics; microglia; in vivo electrophysiology; recognition memory
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.09.042

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. [Display omitted] •Mice mimicking the etiology of mental illness have dysregulated prefrontal network•Weaker beta activation of prefrontal circuits results from superficial layers deficits•Rescue of microglial function restores developing prefrontal function and behavior•Early prefrontal dysfunction relates to later-emerging cognitive performance In a mouse model of mental disorders, Chini et al. dissect an early-emerging prefrontal network dysfunction that subsequently gives rise to cognitive deficits. They show that this deficiency can be rescued by minocycline administration, thus identifying a potential biomarker amenable for future therapies.