Artikel
Deep brain stimulation of the subthalamic nucleus induces a sustained inhibition of the serotonergic system via loss of cell phenotype
Tiefe Hirnstimulation des Nucleus subthalamicus induziert eine dauerhafte Inhibition des serotonergen Systems via Verlust der zellulären Phenotyp
Suche in Medline nach
Autoren
Veröffentlicht: | 25. Mai 2022 |
---|
Gliederung
Text
Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a routine surgical treatment in Parkinson’s disease (PD). Some patients experience debilitating psychiatric side-effects. There is no consensus on the mechanisms underlying mood changes in DBS patients. Recent research has revealed that external stimuli can alter neurotransmitter homeostasis in neurons, which is known as “neurotransmitter respecification”. We addressed if this could be a mechanism by which STN DBS suppresses the serotonergic (5-HT) function in the dorsal raphe nucleus (DRN) and causes behavioural alterations.
Methods: We used transgenic ePet-Cre mice that allowed selective investigation of DRN 5-HT neurons by expression of yellow fluorescence protein as well as the calcium (Ca2+) indicator GCaMP6s. A parkinsonian model was generated by methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Mice received bilateral STN DBS electrodes for long-term in vivo stimulation. Behavioural assessments, in vivo fiber photometry and post-mortem immunohistochemistry for tryptophan hydroxylase-2 (TPH2) expression, the rate limiting enzyme in 5-HT synthesis, were performed.
Results: MPTP treated mice demonstrated a behavioral and histological PD phenotype, with static and dynamic gait impairments (e.g. reduced speed and increased stance) and significant loss of dopamine neurons in the substantia nigra pars compacta (-60%; p<0.05). STN DBS animals exhibited behavioural despair with an increased immobility time (139.6 ± 14.4 sec) in the forced swim test compared to sham stimulated animals (88.9 ± 15.1; p<0.05). In vivo fiber photometry showed significant reduced Ca2+ signaling in the DRN during STN DBS (p<0.05). Stereological cell count of double labelled 5-HT neurons for yellow fluorescent protein and TPH2 revealed a significant decrease in cell numbers in STN DBS treated mice compared to sham controls in parkinsonian (1670±144 vs 712±50) and naïve groups (1590± 141 vs 518±83; p<0.05).
Conclusion: Altogether STN DBS resulted in behavioural despair with simultaneous reduced Ca2+ signaling and loss of immunohistochemical expression of 5-HT neurons in the DRN. Since Ca2+ signaling is crucial in mediating neurotransmitter respecification and long-term STN DBS resulted in a loss of 5-HT phenotype, neurotransmitter respecification may be a mechanism that contributes to the effects of DBS therapy.