Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in<i>Arc/Arg3.1</i>Deficient Mice

Abstract

<i>Arc/Arg3.1</i>, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional <i>Arc/Arg3.1</i> knock-out (KO) mice to investigate the causal relationship between <i>Arc/Arg3.1</i> deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using <i>in vivo</i> local field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in which <i>Arc/Arg3.1</i> was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in which <i>Arc/Arg3.1</i> was deleted during late postnatal development. Our data show that constitutive <i>Arc/Arg3.1</i> KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal of <i>Arc/Arg3.1 per se</i> does not cause schizophrenia-like behavior. Prenatal or perinatal deletion of <i>Arc/Arg3.1</i> alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of <i>Arc/Arg3.1</i> rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.<b>SIGNIFICANCE STATEMENT</b> The activity-regulated and memory-linked gene <i>Arc/Arg3.1</i> has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss of <i>Arc/Arg3.1</i> can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of <i>Arc/Arg3.1</i> before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of <i>Arc/Arg3.1</i> does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation of <i>Arc/Arg3.1</i> might critically imbalance brain networks and lead to emergence of schizophrenia.