Individual differences in stereotypy and neuron subtype translatome with TrkB deletion

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Motor stereotypies in early-onset neuropsychiatric diseases are linked to dysregulated basal ganglia direct-pathway activity.
• Impaired neuronal structure and network connectivity disruptions are implicated in stereotypy.
• The precise neurobiological mechanisms causing direct-pathway neuron disconnectivity in stereotypy are not fully understood.

Purpose of the Study:

• To investigate the neurobiological mechanisms underlying motor stereotypies in a mouse model with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB).
• To identify molecular alterations in D1-medium spiny neurons (D1-MSNs) associated with repetitive behaviors.

Main Methods:

• Utilized a D1-Cre-flTrkB mouse line exhibiting stereotypy-like behaviors (rotations, head tics).
• Employed chemogenetic inhibition of dorsal striatum D1-MSNs to assess behavioral impact.
• Performed RNA sequencing of ribosome-associated mRNA (translatome analysis) on D1-MSNs from affected and unaffected mice.
• Conducted detailed gene expression analysis and examined neuronal morphology.

Main Results:

• Chemogenetic inhibition of D1-MSNs reduced repetitive behaviors in mice.
• Translatome analysis revealed significant alterations in genes related to neuronal projection and synaptic structure in mice with stereotypy.
• Morphological examination showed dendritic atrophy and dendritic spine loss in D1-MSNs of mice exhibiting repetitive behaviors.

Conclusions:

• Phenotype-specific molecular and morphological alterations in D1-MSNs are associated with stereotypy behavior in mice.
• These findings provide insights into the neurobiological underpinnings of motor stereotypies.
• The study highlights the role of TrkB signaling and D1-MSN function in repetitive behaviors.