Transient knock-down of prefrontal DISC1 in immune-challenged mice causes abnormal long-range coupling and cognitive dysfunction throughout development

Abstract

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 in utero 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 PFC E mice, both sexes). Combining in vivo electrophysiology and neuroanatomy with behavioral testing, we show that G PFC 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 PFC 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.