Transient Knock-Down of Prefrontal DISC1 in Immune-Challenged Mice Causes Abnormal Long-Range Coupling and Cognitive Dysfunction throughout Development

• Published in: The Journal of neuroscience Vol. 39; no. 7; pp. 1222 - 1235
• Main Authors: Xu, Xiaxia, Chini, Mattia, Bitzenhofer, Sebastian H, Hanganu-Opatz, Ileana L
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 13.02.2019
• Subjects: Age; Anatomy; Animals; Behavior, Animal - physiology; Brain; Brain architecture; Circuits; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - psychology; Coupling; Dendritic branching; Dendritic spines; Disc1 protein; Electrophysiology; Electroporation; Environmental stress; Exploratory Behavior - physiology; Female; Gene Knockdown Techniques; Hippocampus; Hippocampus - cytology; Hippocampus - growth & development; Immune response; In vivo methods and tests; Memory; Mental disorders; Mice; Mice, Inbred C57BL; Neonates; Nerve Tissue Proteins - genetics; Neural Pathways - growth & development; Prefrontal cortex; Prefrontal Cortex - cytology; Prefrontal Cortex - growth & development; Pregnancy; Prenatal Exposure Delayed Effects; Pyramidal cells; Pyramidal Cells - ultrastructure; Recognition, Psychology - physiology; Schizophrenia; Spine; prefrontal–hippocampal communication; development; network oscillations; DISC1; prefrontal maturation
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2170-18.2018

Compromised brain development has been hypothesized to account for mental illness. This concept was underpinned by the function of the molecule disrupted-in-schizophrenia 1 (DISC1), which represents an intracellular hub of developmental processes and has been related to cognitive dysfunction in psychiatric disorders. Mice with whole-brain DISC1 knock-down show impaired prefrontal-hippocampal function and cognitive abilities throughout development and at adulthood, especially when combined with early environmental stressors, such as maternal immune activation (MIA). However, the contribution of abnormal DISC1-driven maturation of either prefrontal cortex (PFC) or hippocampus (HP) to these deficits is still unknown. Here, we use electroporation to restrict the DISC1 knock-down to prefrontal layer II/III pyramidal neurons during perinatal development and expose these mice to MIA as an environmental stressor (dual-hit G E mice, both sexes). Combining electrophysiology and neuroanatomy with behavioral testing, we show that G E mice at neonatal age have abnormal patterns of oscillatory activity and firing in PFC, but not HP. Abnormal firing rates in PFC of G E mice relate to sparser dendritic arborization and lower spine density. Moreover, the long-range coupling within prefrontal-hippocampal networks is decreased at this age. The transient prefrontal DISC1 knock-down was sufficient to permanently perturb the prefrontal-hippocampal communication and caused poorer recognition memory performance at pre-juvenile age. Thus, developmental dysfunction of prefrontal circuitry causes long-lasting disturbances related to mental illness. Hypofrontality is considered a main cause of cognitive deficits in mental disorders, yet the underlying mechanisms are still largely unknown. During development, long before the emergence of disease symptoms, the functional coupling within the prefrontal-hippocampal network, which is the core brain circuit involved in cognitive processing, is reduced. To assess to which extent impaired prefrontal development contributes to the early dysfunction, immune-challenged mice with transient DISC1 knock-down confined to PFC were investigated in their prefrontal-hippocampal communication throughout development by electrophysiology and behavioral testing. We show that perturbing developmental processes of prefrontal layer II/III pyramidal neurons is sufficient to diminish prefrontal-hippocampal coupling and decrease the cognitive performance throughout development.