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bioRxiv · 10.1101/2022.02.20.481207

Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala

Nagaraja, C.·Chen, L.·Daniels, S.·Meyerdirk, L.·Steiner, J. A.·Galvis, M. L. E.·Henderson, M.·Brundin, P.·Chu, H.-y.
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Abstract

The presynaptic protein -synuclein (Syn) has been suggested to be involved in the pathogenesis of Parkinsons disease (PD). In PD, the amygdala is prone to develop insoluble Syn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how Syn aggregates affect amygdala function is unknown. In this study, we examined Syn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that Syn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of Syn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that Syn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble Syn, which suggests that lower levels of soluble Syn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in Syn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of Syn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

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Nagaraja, C., Chen, L., Daniels, S., Meyerdirk, L., Steiner, J. A., Galvis, M. L. E., Henderson, M., Brundin, P., Chu, H.-y.. 2022-02-20. Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala. https://doi.org/10.1101/2022.02.20.481207

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