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.

Developmental decrease of entorhinal-hippocampal communication in immune-challenged DISC1 knockdown mice

“…In line with previous studies 25 , 27 , 28 , firing and coupling deficits at pre-juvenile age might reflect abnormal circuit wiring initiated at earlier stages of development. To test this hypothesis, we investigated the activity patterns within entorhinal-hippocampal-prefrontal networks in neonatal (P8-10) CON ( n = 14) and GE ( n = 14) mice (Fig.…”

“…Taken together, these results indicate that already at pre-juvenile age the LEC-dependent associative recognition memory is impaired in GE mice. This cognitive deficit complements the previously reported poor performance in other non-associative recognition tasks 25 , 27 , 28 .…”

Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction

“…Three mechanisms might cause these early deficits: (1) local disruption of prefrontal circuits, (2) local disruption of hippocampal circuits, and/or (3) abnormal long-range communication between PFC and HP. We previously confirmed the first two mechanisms and reported that (1) layer 2/3 pyramidal neurons in PFC experienced excessive microglia-induced synaptic pruning leading to impaired β-γ oscillations ( Chini et al, 2020 ) and (2) the sharp-waves, firing, and network activity in hippocampal CA1 area are decreased in GE mice ( Xu et al, 2021 ). Here, we address the third hypothesis and investigate the long-range connectivity between HP and PFC throughout development in dual-hit GE mice.…”

“…We previously showed that these deficits emerge already early in life, at a developmental stage corresponding to neonatal period in mice (first postnatal week) and third gestational trimester in humans ( Clancy et al, 2001 ). Dual-hit GE mice mimicking both the genetic [mutation of the intracellular hub of developmental processes disrupted-in-schizophrenia 1 (DISC1) gene; Brandon and Sawa, 2011 ] and the environmental [challenge by maternal immune activation (MIA)] background that has been related to mental illness, have abnormal patterns of early electrical activity both in PFC and HP ( Hartung et al, 2016 ; Xu et al, 2019 , 2021 ; Chini et al, 2020 ). Additionally, prefrontal-hippocampal coupling through synchrony of oscillatory activity as well as directed HP-to-PFC interactions are diminished.…”

The Logic of Developing Neocortical Circuits in Health and Disease

“…In several developmental mouse models of mental disorders, b -g prefrontal oscillations are impaired from the first few postnatal days until adulthood (Xu et al, 2019;Chini et al, 2020;Xu et al, 2020). Severely simplified dendritic arborization, as well as decreased spine density and firing rate of L2/3 pyramidal cells underlie these abnormalities.…”