Synaptic location is a determinant of the detrimental effects of [alpha]-synuclein pathology to glutamatergic transmission in the basolateral amygdala

• Published in: eLife Vol. 11
• Main Authors: Chen, Liqiang, Nagaraja, Chetan, Daniels, Samuel, Fisk, Zoe A, Dvorak, Rachel, Meyerdirk, Lindsay, Steiner, Jennifer A, Escobar Galvis, Martha L, Henderson, Michael X, Rousseaux, Maxime WC, Brundin, Patrik, Chu, Hong-Yuan
• Format: Journal Article
• Language: English
• Published: eLife Science Publications, Ltd 01.07.2022
• Subjects: Analysis; Brain; Glutamate; United Kingdom
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.78055

The presynaptic protein [alpha]-synuclein ([alpha]Syn) has been suggested to be involved in the pathogenesis of Parkinson's disease (PD). In PD, the amygdala is prone to develop insoluble [alpha]Syn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how [alpha]Syn aggregates affect amygdala function is unknown. In this study, we examined [alpha]Syn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that [alpha]Syn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1.sup.+) terminals in the mouse BLA, which is consistent with higher levels of [alpha]Syn expression in vGluT1.sup.+ glutamatergic neurons in the cerebral cortex relative to the vGluT2.sup.+ glutamatergic neurons in the thalamus. We found that [alpha]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.sup.+ axon terminals exhibited decreased levels of soluble [alpha]Syn, which suggests that lower levels of soluble [alpha]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 [alpha]Syn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of [alpha]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.