Knock-Down of Hippocampal DISC1 in Immune-Challenged Mice Impairs the Prefrontal-Hippocampal Coupling and the Cognitive Performance Throughout Development

Abstract

Disrupted-in-schizophrenia 1 (DISC1) gene represents an intracellular hub of developmental processes. When combined with early environmental stressors, such as maternal immune activation, but not in the absence of thereof, whole-brain DISC1 knock-down leads to memory and executive deficits as result of impaired prefrontal-hippocampal communication throughout development. While synaptic dysfunction in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling, the contribution of hippocampus (HP) is still unknown. Here, we aim to fill this knowledge gap by combining in vivo electrophysiology and optogenetics with morphological and behavioral assessment of immune-challenged mice with DISC1 knock-down either in the whole brain (GE) or restricted to pyramidal neurons in hippocampal CA1 area (GHPE). We found abnormal network activity, sharp-waves, and neuronal firing in CA1 that complement the deficits in upper layer of PFC. Moreover, optogenetic activating CA1 pyramidal neurons fails to activate the prefrontal local circuits. These deficits that persist till prejuvenile age relate to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in HP leads to poorer recognition memory at prejuvenile age. Thus, DISC1-controlled developmental processes in HP in immune-challenged mice are critical for circuit function and cognitive behavior.

Keywords: DISC1; development; hippocampal maturation; optogenetics; prefrontal–hippocampal synchrony.