Sparser and less efficient connectivity account for developmental network dysfunction in a mouse model of psychiatric disorders

Abstract

The hippocampal-prefrontal network decoupling, which starts long before detectable symptomatology, has been implicated in the pathophysiology of neuropsychiatric disorders. Characteristics of the long-range connectivity between hippocampus and prefrontal cortex during development and its deficits in mental diseases are poorly understood. To fill this knowledge gap, combined in vivo and in vitro electrophysiology and optogenetic with in-depth morphological and behavior assessment were employed to dissect cellular mechanisms underlying hippocampal-prefrontal synchrony. The intermediate/ventral hippocampus is found to be coupled more strongly with the prefrontal cortex than the dorsal hippocampus. Furthermore, we show that theta coupling within the hippocampal-prefrontal network is driven by prefrontal cortex-projecting pyramidal neurons in CA1, as activation of these neurons at theta rhythm leads to entrainment of the local prefrontal circuit. Employing a mouse model of combined genetic and environmental risk factors, we report that the hippocampus exhibits morphological and functional disturbances, characterized by simplified dendritic arborization, reduced synaptic density of CA1 neurons, reduced sharp waves and neuronal firing, already at neonatal age. These deficits are replicated by restricting DISC1 mutation to a subset of CA1 pyramidal neurons. Reduced hippocampal drive to the prefrontal cortex throughout development, characterized by sparser axonal projections and less efficiency of these axons, is one mechanism of hippocampal-prefrontal decoupling and is predictive of cognitive abnormalities at pre-juvenile age. The involvement of the lateral entorhinal cortex in regulating hippocampal-prefrontal communication has been investigated. We show that the lateral entorhinal cortex modulates prefrontal oscillations directly and indirectly. While the direct pathway is largely intact in the mouse model mimicking aspects of etiology of psychiatric illness, the indirect pathway is impaired specifically through the decreased entorhinal drive of the hippocampal circuit. Less and inefficient entorhinal projections that cannot relay information from lateral entorhinal cortex to prefrontal cortex are observed in hippocampus of disease mice, further disturbing the maturation of prelimbic circuit and being another fundamental mechanism underlying the cognitive disruption in mental disorders. These results open up mechanistic insights into understanding the communication between hippocampus and prefrontal cortex throughout development. Elucidation of cellular substrates that underlie hippocampal-prefrontal information processing is crucial for understanding cognitive functions, especially their impairments in psychiatric diseases.