Corticostriatal circuit defects in Hoxb8 mutant mice

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Hoxb8 mutant mice display compulsive grooming, resembling human trichotillomania, an obsessive-compulsive disorder (OCD)-spectrum disorder.
• Microglia are the primary detectable cells of the Hoxb8 cell lineage in the mouse brain, suggesting their role in this neuropsychiatric disorder.

Purpose of the Study:

• To investigate if Hoxb8 mutations in microglia lead to neural circuit dysfunctions.
• To explore the link between Hoxb8-microglia defects and neuropsychiatric symptoms.

Main Methods:

• Golgi staining, ultra-structural analysis, and electrophysiological studies were performed on Hoxb8 mutant mice.
• Behavioral assessments included evaluations of grooming, anxiety, and social interaction.
• Pharmacological treatment with fluoxetine was administered to assess therapeutic effects.

Main Results:

• Hoxb8 mutants exhibit corticostriatal circuit defects, including excess dendritic spines and pre/postsynaptic structural abnormalities.
• Electrophysiological findings revealed defects in long-term potentiation and miniature postsynaptic currents.
• Mutant mice showed hyperanxiety and social behavioral deficits, similar to models of OCD and autism spectrum disorders (ASDs).
• Fluoxetine treatment significantly reduced compulsive grooming, hyperanxiety, and social impairments.

Conclusions:

• Defective Hoxb8-expressing microglia induce neural circuit dysfunctions, contributing to OCD and ASD-like behaviors.
• These findings establish a link between microglia-specific defects and neuronal dysfunction in neuropsychiatric disorders.
• Targeting Hoxb8-microglia presents a potential therapeutic strategy for OCD and ASDs.