Characterizing the hippocampal synaptic and sleep abnormalities of a mouse model of human chromosome 16p11.2 microdeletion

2018-07-27The pathophysiology of neurodevelopmental disorders is often observed early in infancy and toddlerhood. Mouse models of syndromic disorders have provided insight regarding mechanisms of action, but most studies have focused on characterization in juveniles and adults. Insight into developmental trajectories, particularly those related to circuit and synaptic function, will likely yield important information regarding disorder pathogenesis that leads to symptom progression. Chromosome 16p11.2 microdeletion is one of the most common copy number variations associated with a spectrum of neurodevelopmental disorders. Yet, how haploinsufficiency of chr16p11.2 affects early synaptic maturation and function is unknown. To address this knowledge gap, the present study focused on three key components of circuit formation and function—basal synaptic transmission, local circuit function, and maturation of glutamatergic synapses—in developing hippocampal CA1 neurons in a chr16p11.2 microdeletion mouse model. The data demonstrate increased excitability, imbalance in excitation and inhibition, and accelerated maturation of glutamatergic synapses in heterozygous deletion mutant CA1 neurons. Given the critical role of early synaptic development in shaping neuronal connectivity and circuitry formation, these newly identified synaptic abnormalities in chr16p11.2 microdeletion mice may contribute to altered developmental trajectory and function of the developing brain. ❧ Sleep disturbance is very prevalent among patients with neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASDs) and attention deficit-hyperactivity disorder (ADHD). Evidence from genome-wide association studies indicates that chromosomal copy number variations (CNVs) are associated with increased prevalence of these neurodevelopmental disorders. Several studies on mouse models of chr16p11.2 microdeletion have demonstrated impairments in synaptic transmission and local circuitry function in the hippocampus and striatum. However, it has not been adequately addressed if chr16p11.2 microdeletion is associated with system level abnormalities in mice, such as sleep and neuronal oscillation. To address this knowledge gap, the present study investigated sleep architectures and oscillation patterns in a mouse model of human chr16p11.2 microdeletion. Polysomnographic recording revealed reduced non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, decreased number of REM bouts, shortened REM epoch duration, and altered NREM to REM transition in heterozygous mutant mice. The mutant mice also showed significant alterations in EEG oscillation patterns, involving several frequency classes in different vigilant states. In addition, the ventrolateral periaqueductal gray matter (vlPAG)-projecting GABAergic neurons in lateral paragigantocellular nucleus (LPGi), one of the main REM-on center, from heterozygous mutant mice were less excitable compared to wildtype neurons. In sum, our study demonstrated significant differences in sleep architecture, oscillation patterns, and candidate nucleus in the chr16p11.2 mouse model