Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Heterozygous deletion of the TSHZ3 gene is linked to autism spectrum disorder (ASD).
• TSHZ3 is a transcription factor highly expressed in cortical projection neurons (CPNs).
• Mice with Tshz3 haploinsufficiency exhibit ASD-like behaviors and corticostriatal dysfunction.

Purpose of the Study:

• To investigate the temporal and spatial requirements of TSHZ3 during brain development.
• To understand the role of TSHZ3 deficiency in ASD pathogenesis.
• To characterize a novel conditional Tshz3 knockout mouse model for ASD research.

Main Methods:

• Generated a conditional Tshz3 knockout mouse model by crossing Tshz3^flox/flox with CaMKIIalpha-Cre mice.
• Utilized a multilevel approach including genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics.
• Analyzed gene expression changes in CPNs of knockout mice.

Main Results:

• Conditional Tshz3 knockout mice displayed altered cortical gene expression, with many genes linked to ASD.
• Observed electrophysiological and synaptic alterations in CPNs and impaired corticostriatal transmission.
• Demonstrated significant ASD-like behavioral deficits in the knockout mice.

Conclusions:

• TSHZ3 plays a critical postnatal role in corticostriatal circuitry development and function.
• Dysfunction in these circuits may be a key factor in ASD.
• The novel conditional Tshz3 knockout mouse model offers a platform for studying ASD and potential early postnatal therapeutics.