Altered Neocortical Dynamics in a Mouse Model of Williams\u2013Beuren Syndrome

Miguel Dasilva,Alessandra Camassa,Maria V Sanchez-Vives,Alvaro Navarro-Guzman,Alberto Muñoz-Cespedes,Paula Ortiz-Romero,Victoria Campuzano

doi:10.1007/s12035-019-01732-4

Abstract

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by moderate intellectual disability and learning difficulties alongside behavioral abnormalities such as hypersociability. Several structural and functional brain alterations are characteristic of this syndrome, as well as disturbed sleep and sleeping patterns. However, the detailed physiological mechanisms underlying WBS are mostly unknown. Here, we characterized the cortical dynamics in a mouse model of WBS previously reported to replicate most of the behavioral alterations described in humans. We recorded the laminar local field potential generated in the frontal cortex during deep anesthesia and characterized the properties of the emergent slow oscillation activity. Moreover, we performed micro-electrocorticogram recordings using multielectrode arrays covering the cortical surface of one hemisphere. We found significant differences between the cortical emergent activity and functional connectivity between wild-type mice and WBS model mice. Slow oscillations displayed Up states with diminished firing rate and lower high-frequency content in the gamma range. Lower firing rates were also recorded in the awake WBS animals while performing a marble burying task and could be associated with the decreased spine density and thus synaptic connectivity in this cortical area. We also found an overall increase in functional connectivity between brain areas, reflected in lower clustering and abnormally high integration, especially in the gamma range. These results expand previous findings in humans, suggesting that the cognitive deficits characterizing WBS might be associated with reduced excitability, plus an imbalance in the capacity to functionally integrate and segregate information.

Highlights

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder that results from the heterozygous deletion of 26–28 contiguous genes at chromosome7q11.23 and is characterized by mild to moderate intellectual disability, learning difficulties, and hypersociability [1]
We recorded the spontaneous local field potential (LFP) activity generated in the frontal cortex of 9 WBS mice and 8 WT littermates under ketamine anesthesia
We found that the duration of Up and Down states was not different between WBS and WT mice, which was reflected in a similar Slow oscillations (SO) frequency

Summary

Introduction

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder that results from the heterozygous deletion of 26–28 contiguous genes at chromosome7q11.23 and is characterized by mild to moderate intellectual disability, learning difficulties, and hypersociability [1]. Abnormalities in the structure of the amygdala, hippocampus, and cerebral cortex have been described and related to the neurocognitive profile [2]. Anomalies in the cytoarchitecture of the cerebral cortex, columnar orientation and cell and dendritic density, have been reported [3,4,5,6]. Sleep structure and efficiency have been described as altered in WBS. Sleep cycles are fragmented and disorganized, REM sleep is decreased, and the frequency content of NREM sleep is unbalanced [7, 8]. Alterations in functional connectivity have been described during resting states and natural sleep in individuals suffering from WBS [9,10,11]

Objectives

Results

Conclusion