Altered Neocortical Dynamics in a Mouse Model of Williams–Beuren Syndrome

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.

Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

“…The neurocognitive profile of WBS patients has been related with abnormalities in the structure of the hippocampus and the cerebral cortex (Reiss et al, 2000). Previous studies showed that CD animals present significant alterations in different cortical and hippocampal regions (Segura-Puimedon et al, 2014;Borralleras et al, 2015;Ortiz-Romero et al, 2018;Dasilva et al, 2020). Substantial structural reorganization of various areas of the adult mouse brain (including the hippocampus and motor cortex) has been described after a relatively short period of motor skills training using the rotarod (Scholz et al, 2015).…”

Modulation of cortical slow oscillatory rhythm by GABAB receptors: an in vitro experimental and computational study

“…2017), Parkinson's (Little & Brown, 2014), autism (Rubenstein & Merzenich, 2003), Williams–Beuren syndrome (Dasilva et al . 2020) or Down syndrome (Ruiz‐Mejias et al . 2016), among others.…”

Cortical Activity and Rhythmic Patterns in Mouse Models of Aging and Alzheimer’s Disease

“…This suggests that NMDAR activation prevents hypersynchronization under physiological conditions [114]. Reduction of firing rates in the local network is most often associated with a decrease in the synchronization in the beta-gamma range in several cases; for example, cortical inhibitory alteration and overinhibition in a Down syndrome model [83], increased functional connectivity in a Williams-Beuren syndrome model [115], when comparing area-specific cortical activity [17], or even by the effect of temperature modulation [116]. Further to this, altered cholinergic input originating from the forebrain may play a role in network desynchronization [117], given that a lack of acetylcholine in the cortex directly leads to a loss of gamma rhythm synchronization (21-70 Hz) [118].…”