Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome

Abstract

Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.

Ocular Dominance Plasticity in Binocular Primary Visual Cortex Does Not Require C1q

“…This observation suggests that Arc in situs can be used as a proxy to measure ODP. Indeed, both enhanced and reduced ODP detected using this method has been confirmed using alternative techniques (Syken et al, 2006;Kanold et al, 2009;William et al, 2012William et al, , 2017Djurisic et al, 2013;Bochner et al, 2014). We therefore used the Arc in situ method to examine ODP in mice lacking C1qa.…”

“…Sections without signal in L2/3 of V1b were discarded. The length of the Arcpositive zone in L4 and L2/3 was calculated in ImageJ (NIH) as the full-width at half-maximum (FWHM), as has been done previously (William et al, 2017). To measure the FWHM, the half-maximum was first determined.…”

“…After 4 d of MD, the animals were light stimulated and their brains collected. We then performed RNAscope fluorescence in situ hybridization against Arc, and quantified the length of the binocular zone in L2/3 and L4 by measuring the FWHM (William et al, 2017; Fig. 9A).…”

Longitudinal Learning Diagnosis: Minireview and Future Research Directions

“…Overall, there are still many issues related to longitudinal learning diagnosis that are worthy of discussion. In view of the advantages of longitudinal learning diagnosis compared with cross-sectional learning diagnosis, the former is more in line with the idea of assessment for learning (Wiliam, 2011 ) and the needs of formative assessments.…”

A smaller olfactory bulb in a mouse model of Down syndrome

“…Similar alterations have also been observed in persons with DS. Moreover, Ts65Dn mice present impaired refinement of synaptic connections by olfactory neurons in the OB (William et al, 2017). Accordingly, investigating the OB in the Ts65Dn mouse is relevant to clarify the mechanisms of olfactory impairment in DS.…”