RT Journal Article
SR Electronic
T1 Disturbed prefrontal cortex activity in the absence of schizophrenia-like behavioral dysfunction in Arc/Arg3.1 deficient mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 0623-19
DO 10.1523/JNEUROSCI.0623-19.2019
A1 Xiaoyan Gao
A1 Jasper Grendel
A1 Mary Muhia
A1 Sergio Castro-Gomez
A1 Ute Süsens
A1 Dirk Isbrandt
A1 Matthias Kneussel
A1 Dietmar Kuhl
A1 Ora Ohana
YR 2019
UL http://www.jneurosci.org/content/early/2019/09/05/JNEUROSCI.0623-19.2019.abstract
AB Arc/Arg3.1, 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 utilized male and female constitutive and conditional Arc/Arg3.1 knock out (KO) mice to investigate the causal relationship between Arc/Arg3.1 deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using in vivo local field potential (LFP) recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (Early-cKO) mice, in which Arc/Arg3.1 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 Arc/Arg3.1 was deleted during late postnatal development. Our data show that constitutive Arc/Arg3.1 KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an enviromental stressor, failed to induce deficits in socialbility or sensorimotor gating in adult KO mice. Thus, genetic removal of Arc/Arg3.1 per se does not cause schizophrenia-like behavior. Pre- or perinatal deletion of Arc/Arg3.1 alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of Arc/Arg3.1 rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.Significance StatementThe activity-regulated and memory-linked gene Arc/Arg3.1 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 Arc/Arg3.1 can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of Arc/Arg3.1 before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of Arc/Arg3.1 does not cause schizophrenia, even when combined with an environmental assault. It remains to be seen whether misregulation of Arc/Arg3.1 might critically imbalance brain networks and lead to emergence of schizophrenia.