Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
Mol Psychiatry. 2020-05-04; :
DOI: 10.1038/s41380-020-0746-0
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Engeln M(1), Song Y(2), Chandra R(1), La A(1), Fox ME(1), Evans B(1), Turner MD(1), Thomas S(1), Francis TC(1), Hertzano R(1)(2)(3), Lobo MK(4).
Author information:
(1)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, MD, USA.
(2)Institute for Genome Sciences, University of Maryland School of Medicine,
Baltimore, MD, USA.
(3)Department of Otorhinolaryngology Head and Neck Surgery, University of
Maryland School of Medicine, Baltimore, MD, USA.
(4)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, MD, USA. .
Motor stereotypies occurring in early-onset neuropsychiatric diseases are
associated with dysregulated basal ganglia direct-pathway activity. Disruptions
in network connectivity through impaired neuronal structure have been implicated
in both rodents and humans. However, the neurobiological mechanisms leading to
direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We
have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion
from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows
repetitive rotations and head tics with juvenile onset. Here we demonstrate these
behaviors may be associated with abnormal direct-pathway activity by reducing
rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny
neurons (D1-MSNs) in both juvenile and young-adult mice. Taking advantage of
phenotypical differences in animals with similar genotypes, we then interrogated
the D1-MSN specific translatome associated with repetitive behavior by using RNA
sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by
multiplexed gene expression assessment revealed profound alterations in neuronal
projection and synaptic structure related genes in stereotypy mice. Examination
of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in
dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results
uncover phenotype-specific molecular alterations in D1-MSNs that relate to
morphological adaptations in mice displaying stereotypy behavior.
DOI: 10.1038/s41380-020-0746-0
PMID: 32366954