Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

Helen Motanis,Dean Buonomano

doi:10.1038/s41598-020-71333-y

Helen Motanis, Dean Buonomano

Open Access

https://doi.org/10.1038/s41598-020-71333-y

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Journal: Scientific Reports	Publication Date: Sep 3, 2020
Citations: 9	License type: open-access

Affiliation: University of California, Los Angeles

Abstract

Fragile X syndrome is a neurodevelopmental disorder associated with a broad range of neural phenotypes. Interpreting these findings has proven challenging because some phenotypes may reflect compensatory mechanisms or normal forms of plasticity differentially engaged by experiential differences. To help minimize compensatory and experiential influences, we used an ex vivo approach to study network dynamics and plasticity of cortical microcircuits. In Fmr1−/y circuits, the spatiotemporal structure of Up-states was less reproducible, suggesting alterations in the plasticity mechanisms governing network activity. Chronic optical stimulation revealed normal homeostatic plasticity of Up-states, however, Fmr1−/y circuits exhibited abnormal experience-dependent plasticity as they did not adapt to chronically presented temporal patterns in an interval-specific manner. These results, suggest that while homeostatic plasticity is normal, Fmr1−/y circuits exhibit deficits in the ability to orchestrate multiple forms of synaptic plasticity and to adapt to sensory patterns in an experience-dependent manner—which is likely to contribute to learning deficits.

Highlights

The sheer diversity of reported neural phenotypes highlights the challenge in determining which phenotypes are a primary consequence of the absence of FMRP, from those that reflect indirect secondary neural phenotypes
These secondary neural phenotypes could reflect: (1) compensatory and homeostatic mechanisms, i.e., genetic redundancy and homeostatic plasticity engaged to compensate for the primary consequences of the lack of FMRP44–46; or (2) normal forms of plasticity shaped by experiential differences, including differences in sensory exploration, social interactions and maternal care
We contrasted Fmr1−/y and Fmr1+/y circuits using two-photon Ca2+-imaging at two ex vivo developmental ages: 11–16 days in vitro (DIV) and [25,26,27,28,29,30] DIV (Figs. 1, 2)

Summary

Introduction

The sheer diversity of reported neural phenotypes highlights the challenge in determining which phenotypes are a primary consequence of the absence of FMRP, from those that reflect indirect secondary neural phenotypes. It is well established that early differences in sensory experience, social interactions and maternal rearing, can alter numerous neural properties throughout life[47,48,49,50,51,52,53]. One approach towards disentangling neural phenotypes that are a direct consequence of the absence of FMRP and those that reflect experiential differences is to study network activity and plasticity in isolated circuits that develop ex vivo. Our results establish a sequence of developmental delays in Fmr1−/y circuits, and importantly show that even when overall Up-state frequency is equivalent between WT and FX circuits, the spatiotemporal structure of the underlying activity is altered These results are consistent with the notion that FXS may reflect the inability to properly orchestrate the multiple forms of plasticity required to generate stable and reproducible spatiotemporal patterns of neural a ctivity[46]. We find that while homeostatic plasticity of Up-states is normal, a form of ex vivo experience-dependent plasticity, that emulates learning, is altered in Fmr1-KO circuits

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Discussion

Conclusion