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Corticostriatal circuit defects in Hoxb8 mutant mice
N Nagarajan1, B W Jones2, P J West3
1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, USA. naveen@genetics.utah.edu.
Abstract:
Hoxb8 mutant mice exhibit compulsive grooming and hair removal dysfunction similar to humans with the obsessive-compulsive disorder (OCD)-spectrum disorder, trichotillomania. As, in the mouse brain, the only detectable cells that label with Hoxb8 cell lineage appear to be microglia, we suggested that defective microglia cause the neuropsychiatric disorder. Does the Hoxb8 mutation in microglia lead to neural circuit dysfunctions? We demonstrate that Hoxb8 mutants contain corticostriatal circuit defects. Golgi staining, ultra-structural and electrophysiological studies of mutants reveal excess dendritic spines, pre- and postsynaptic structural defects, long-term potentiation and miniature postsynaptic current defects. Hoxb8 mutants also exhibit hyperanxiety and social behavioral deficits similar to mice with neuronal mutations in Sapap3, Slitrk5 and Shank3, reported models of OCD and autism spectrum disorders (ASDs). Long-term treatment of Hoxb8 mutants with fluoxetine, a serotonin reuptake inhibitor, reduces excessive grooming, hyperanxiety and social behavioral impairments. These studies provide linkage between the neuronal defects induced by defective Hoxb8-microglia and neuronal dysfunctions directly generated by mutations in synaptic components that result in mice, which display similar pathological grooming, hyperanxiety and social impairment deficits. Our results shed light on Hoxb8 microglia-driven circuit-specific defects and therapeutic approaches that will become essential to developing novel therapies for neuropsychiatric diseases such as OCD and ASDs with Hoxb8-microglia being the central target.
Insights
Defective Hoxb8 microglia cause compulsive grooming and social deficits in mice, mimicking human obsessive-compulsive disorder (OCD). Fluoxetine treatment improved these symptoms, suggesting microglia as a therapeutic target for OCD and autism spectrum disorders (ASDs).
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.
