Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene

• Published in: Nature neuroscience Vol. 21; no. 7; pp. 996 - 1003
• Main Authors: Middleton, Steven J., Kneller, Emily M., Chen, Shuo, Ogiwara, Ikuo, Montal, Mauricio, Yamakawa, Kazuhiro, McHugh, Thomas J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2018; Nature Publishing Group
• Subjects: 42/41; 631/378/1595/1554; 631/378/1595/3922; 631/378/1689/2115; 631/378/2586; 64/60; 9/30; Abnormalities; Action Potentials - physiology; Activation; Animal Genetics and Genomics; Animals; Behavior; Behavior, Animal - physiology; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Care and treatment; Epilepsy; Gene mutation; Genetic aspects; Heterozygote; Hippocampus; Hippocampus (Brain); Hippocampus - physiopathology; Intellectual disabilities; Learning; Male; Memory; Memory Disorders - genetics; Memory Disorders - physiopathology; Memory tasks; Memory, Short-Term - physiology; Mice; Mice, Knockout; Mutation; NAV1.2 Voltage-Gated Sodium Channel - genetics; Nervous system diseases; Neural Pathways - physiopathology; Neurobiology; Neurological diseases; Neurons; Neurons - physiology; Neurophysiology; Neurosciences; Physiology; Science; Sleep - physiology; Spatial analysis; Spatial memory; Spatial Memory - physiology
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-018-0163-8

An accumulating body of experimental evidence has implicated hippocampal replay occurring within sharp wave ripples (SPW-Rs) as crucial for learning and memory in healthy subjects. This raises speculation that neurological disorders impairing memory disrupt either SPW-Rs or their underlying neuronal activity. We report that mice heterozygous for the gene Scn2a , a site of frequent de novo mutations in humans with intellectual disability, displayed impaired spatial memory. While we observed no changes during encoding, to either single place cells or cell assemblies, we identified abnormalities restricted to SPW-R episodes that manifest as decreased cell assembly reactivation strengths and truncated hippocampal replay sequences. Our results suggest that alterations to hippocampal replay content may underlie disease-associated memory deficits. Middleton et al. demonstrate that heterozygous deletion of the frequently mutated Scn2a gene leads to reduced performance in spatial memory tasks in mice, resulting from incomplete sequence reactivation during hippocampal sharp wave ripples.