Common Defects of Spine Dynamics and Circuit Function in Neurodevelopmental Disorders: A Systematic Review of Findings From in Vivo Optical Imaging of Mouse Models

Abstract

In vivo optical imaging is a powerful tool for revealing brain structure and function at both the circuit and cellular levels. Here, we provide a systematic review of findings obtained from in vivo imaging studies of mouse models of neurodevelopmental disorders, including the monogenic disorders fragile X syndrome, Rett syndrome, and Angelman syndrome, which are caused by genetic abnormalities of FMR1, MECP2, and UBE3A, as well as disorders caused by copy number variations (15q11-13 duplication and 22q11.2 deletion) and BTBR mice as an inbred strain model of autism spectrum disorder (ASD). Most studies visualize the structural and functional responsiveness of cerebral cortical neurons to sensory stimuli and the developmental and experience-dependent changes in these responses as a model of brain functions affected by these disorders. The optical imaging techniques include two-photon microscopy of fluorescently labeled dendritic spines or neurons loaded with fluorescent calcium indicators and macroscopic imaging of cortical activity using calcium indicators, voltage-sensitive dyes or intrinsic optical signals. Studies have revealed alterations in the density, stability, and turnover of dendritic spines, aberrant cortical sensory responses, impaired inhibitory function, and concomitant failure of circuit maturation as common causes for neurological deficits. Mechanistic hypotheses derived from in vivo imaging also provide new directions for therapeutic interventions. For instance, it was recently demonstrated that early postnatal administration of a selective serotonin reuptake inhibitor (SSRI) restores impaired cortical inhibitory function and ameliorates the aberrant social behaviors in a mouse model of ASD. We discuss the potential use of SSRIs for treating ASDs in light of these findings.

Experience Recruits MSK1 to Expand the Dynamic Range of Synapses and Enhance Cognition

“…Equally, the increased number of dendritic spines in MSK1 KD mice observed here and in a previous study (Corrêa et al, 2012) suggest that MSK1 influences spine density, either constitutively as a regulator of gene expression or in an activity-dependent manner in response to synaptic activity. This dysregulation of spine number in the MSK1 KD mutant may contribute in particular to the cognitive impairments seen in MSK1 KD mice after enrichment and has parallels with the greater spine density and impaired cognition observed in both human autism spectrum disorder and animal models of autism (Coley and Gao, 2018;Nakai et al, 2018). MSK1 may thus coordinate the neuronal mechanisms and networks supporting synaptic structure, function, plasticity, and cognition through the regulation of gene expression.…”

Encoding of social exploration by neural ensembles in the insular cortex

“…Finally, the structure and function of the IC are known to be altered in various brain disorders, including schizophrenia and ASD. Our study thus provides a cellular basis of insular social function on which future research using mouse models of neuropsychiatric and neurodevelopmental disorders will be grounded [49,50].…”

Imaging the Neural Circuit Basis of Social Behavior: Insights from Mouse and Human Studies

“…Fluorescence monitoring of neural activity optically records signals of fluorescent neural activity reporter molecules within neurons. 5) This technique can be classified into two types in terms of the size of the areas monitored: whole-brain versus local measurements. Recent whole-brain mapping technologies aim to conduct automated, comprehensive mapping of changes in brain activity across the brain at the cellular level.…”

“…The fluorescence changes of calcium indicators are monitored at the local circuit level in freely moving animals by fiber photometry or by miniaturized head-mounted epi-fluorescence microendoscopy, or in head-fixed animals by two-photon laser scanning microscopy, as reviewed elsewhere. 5 , 15) …”