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ANATOMICAL AND FUNCTIONAL PROFILING OF SEROTONERGIC CIRCUITS IN MACHADO-JOSEPH DISEASE
Cármen Vieiraand 10 co-authors
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS04-08PM-254
Presentation
Date TBA
Board: PS04-08PM-254
Event Information
Poster Board
PS04-08PM-254
Poster
View posterAbstract
The cerebellum is essential for maintaining balance and posture, coordinating voluntary movement, and motor learning. Cerebellar dysfunction results in ataxia. Machado-Joseph disease (MJD) or Spinocerebellar Ataxia type 3 (SCA3) is the most common form of dominant ataxia, associated with an expansion of the CAG repeat tract in the coding region of ATXN3. Among the most affected brain regions are the deep cerebellar nuclei (DCN). Currently, there is no therapy available to halt or delay disease progression.
Using a hypothesis-free approach, we previously found that activation of the serotonergic (5-HT) system suppresses MJD-associated proteotoxicity. MJD mice show early firing irregularities in DCN neurons, which are restored by the 5-HT modulator citalopram (CIT). Nonetheless, whether MJD involves primary dysfunction of the 5-HT system remains unknown.
Our analyses show that the dorsal raphe (DR), one of the major sources of 5-HT, is largely preserved in MJD mice, with no significant changes in serotonin transporter (Sert) volume or intensity, 5-HT neuron number, or accumulation of large ATXN3 aggregates. Ongoing studies are examining other serotonergic nuclei and Sert-positive innervation of the DCN. Chemogenetic activation of DR 5-HT neurons starting at 12 weeks did not phenocopy the motor benefits observed with early, chronic CIT treatment, suggesting that an earlier/more widespread activation may be required.
Overall, these findings suggest that serotonergic involvement in MJD may reflect functional alterations rather than overt neurodegeneration. Ongoing fiber photometry experiments monitoring DR 5-HT neuron activity and DCN 5-HT levels during motor behavior, will clarify how 5-HT signaling modulates disease progression.
Using a hypothesis-free approach, we previously found that activation of the serotonergic (5-HT) system suppresses MJD-associated proteotoxicity. MJD mice show early firing irregularities in DCN neurons, which are restored by the 5-HT modulator citalopram (CIT). Nonetheless, whether MJD involves primary dysfunction of the 5-HT system remains unknown.
Our analyses show that the dorsal raphe (DR), one of the major sources of 5-HT, is largely preserved in MJD mice, with no significant changes in serotonin transporter (Sert) volume or intensity, 5-HT neuron number, or accumulation of large ATXN3 aggregates. Ongoing studies are examining other serotonergic nuclei and Sert-positive innervation of the DCN. Chemogenetic activation of DR 5-HT neurons starting at 12 weeks did not phenocopy the motor benefits observed with early, chronic CIT treatment, suggesting that an earlier/more widespread activation may be required.
Overall, these findings suggest that serotonergic involvement in MJD may reflect functional alterations rather than overt neurodegeneration. Ongoing fiber photometry experiments monitoring DR 5-HT neuron activity and DCN 5-HT levels during motor behavior, will clarify how 5-HT signaling modulates disease progression.
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