Abstract

Excitatory-inhibitory imbalance (E/I) is a fundamental mechanism underlying autism spectrum disorders (ASD). TRIM32 is a risk gene genetically associated with ASD. The absence of TRIM32 causes impaired generation of inhibitory GABAergic interneurons, neural network hyperexcitability, and autism-like behavior in mice, emphasizing the role of TRIM32 in maintaining E/I balance, but despite the description of TRIM32 in regulating proliferation and differentiation of cultured mouse neural progenitor cells (NPCs), the role of TRIM32 in cerebral cortical development, particularly in the production of excitatory pyramidal neurons, remains unknown. The present study observed that TRIM32 deficiency resulted in decreased numbers of distinct layer-specific cortical neurons and decreased radial glial cell (RGC) and intermediate progenitor cell (IPC) pool size. We further demonstrated that TRIM32 deficiency impairs self-renewal of RGCs and IPCs as indicated by decreased proliferation and mitosis. A TRIM32 deficiency also affects or influences the formation of cortical neurons. As a result, TRIM32-deficient mice showed smaller brain size. At the molecular level, RNAseq analysis indicated reduced Notch signalling in TRIM32-deficient mice. Therefore, the present study indicates a role for TRIM32 in pyramidal neuron generation. Impaired generation of excitatory pyramidal neurons may explain the hyperexcitability observed in TRIM32-deficient mice.

Highlights

  • The imbalance between excitability and inhibitory activity in brain circuits is one of the key mechanisms underlying neurodevelopmental disorders, such as autism spectrum disorders (ASD), which are characterized by impaired social behaviours and repetitive and stereotypic behaviours [1]

  • TRIM32 is expressed by neural progenitor cells (NPCs), including interneuron progenitors within the developing ventricular zone [10,11,14]

  • In order to determine which types of NPCs express TRIM32, we immunostained for the markers Sox2

Read more

Summary

Introduction

The imbalance between excitability and inhibitory activity in brain circuits is one of the key mechanisms underlying neurodevelopmental disorders, such as autism spectrum disorders (ASD), which are characterized by impaired social behaviours and repetitive and stereotypic behaviours [1]. The E/I balance in the brain is coordinated by glutamatergic pyramidal neurons and GABAergic interneurons. The pyramidal neurons are arranged in six layers, while the inhibitory interneurons are scattered. There are definite temporal and spatial orders in which excitatory pyramidal neurons and inhibitory interneurons are generated [2,3,4]. The later born cortical neurons will move across the earlierborn neurons which reside in the deep laminar of cortex [6]. Any disturbances during these sequential processes will lead to developmental disorders such as ASD

Methods
Results
Discussion
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.