LiCl treatment leads to long-term restoration of spine maturation and synaptogenesis in adult Tbr1 mutants

Siavash Fazel Darbandi,Kevin J Bender,John L R Rubenstein,Emily Ling-Lin Pai,Andrew D Nelson

doi:10.1186/s11689-022-09421-5

Abstract

BackgroundTbr1 encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. Tbr1 is expressed in the postmitotic excitatory neurons of the deep neocortical layers 5 and 6. Postnatally and neonatally, Tbr1 conditional mutants (CKOs) have immature dendritic spines and reduced synaptic density. However, an understanding of Tbr1’s function in the adult mouse brain remains elusive.MethodsWe used conditional mutagenesis to interrogate Tbr1’s function in cortical layers 5 and 6 of the adult mouse cortex.ResultsAdult Tbr1 CKO mutants have dendritic spine and synaptic deficits as well as reduced frequency of mEPSCs and mIPSCs. LiCl, a WNT signaling agonist, robustly rescues the dendritic spine maturation, synaptic defects, and excitatory and inhibitory synaptic transmission deficits.ConclusionsLiCl treatment could be used as a therapeutic approach for some cases of ASD with deficits in synaptic transmission.

Highlights

Genetic heterogeneity and phenotypic pleiotropy have complicated efforts in understanding the underlying biology of autism spectrum disorder (ASD) [1, 2]
Towards evaluating whether lithium chloride (LiCl) rescue could be relevant for the treatment of human TBR1 mutant patients, we evaluated whether Tbr1 mutant mice have (1) dendritic spine and synaptic deficits that persist into adulthood, (2) whether LiCl treatment can rescue the phenotype in the older animals, and (3) whether LiCl treatment rescued synaptic transmission
We have demonstrated that the LiCl rescue of the spine and synaptic density in the Tbr1layer5 and Tbr1layer6 Conditional nock-out (CKO) mutants is sustained 6 months after the LiCl injection, which indicates the long-term efficacy of LiCl treatment on rescuing spine and synaptic density deficits

Summary

Introduction

Genetic heterogeneity and phenotypic pleiotropy have complicated efforts in understanding the underlying biology of autism spectrum disorder (ASD) [1, 2]. Systems analyses suggest that the expression of ASD risk genes have important functions in mid-fetal deep layer cortical excitatory neurons and that disruption may contribute to ASD pathophysiology [2]. Analyses of co-expression networks of ASD-risk genes provide evidence that reduced dosage of genes, such as Tbr, may underlie ASD by disrupting processes in immature projection neurons of deep cortical layers during human mid-fetal development [2]. Two of the TBR1 de novo mutations generate truncated proteins that lack a functional DNA-binding T-box domain [4]. These two truncated TBR1 mutants lose their ability to regulate transcription, have an altered intracellular distribution, and fail to. Tbr encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. An understanding of Tbr1’s function in the adult mouse brain remains elusive

Methods

Results

Conclusion