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 and has been related to cognitive dysfunction in psychiatric disorders. Mice with whole-brain DISC1 knock-down show memory and executive deficits as result of impaired prefrontal-hippocampal communication throughout development, especially when combined with early environmental stressors, such as maternal immune activation (MIA). While synaptic dysfunction of layer 2/3 pyramidal neurons in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling in these mice, it is still unclear whether the hippocampus (HP) is also compromised during development. 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 CA1 area of intermediate/ventral HP (i/vHP) (GHPE). Both groups of mice show abnormal network activity, sharp-waves (SPWs) and neuronal firing in CA1 area. Moreover, optogenetic stimulation of CA1 pyramidal neurons fails to activate the local circuits in the neonatal PFC. These deficits that persist until pre-juvenile development are due to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in immune-challenged mice leads to poorer recognition memory at pre-juvenile age. Thus, besides PFC, hippocampal CA1 area has a critical role for the developmental miswiring and long-lasting cognitive impairment related to mental illness. Significance StatementDevelopmental miswiring within prefrontal-hippocampal networks has been proposed to account for cognitive impairment in mental disorders. Indeed, during development, long before the emergence of cognitive deficits, the functional coupling within these networks is reduced in mouse models of disease. However, the cellular mechanisms of dysfunction are largely unknown. Here we combine in vivo electrophysiology and optogenetics with behavioral assessment in immune-challenged mice with hippocampus-confined DISC1 knock-down and show that pyramidal neurons in CA1 area are critical for the developmental dysfunction of prefrontal-hippocampal communication and cognitive impairment.