Abstract
α-Synuclein (αSyn) is a soluble protein enriched at presynaptic boutons and its abnormal aggregation is a hallmark of Parkinson’s disease (PD). The amygdala shows selective vulnerability to the formation of insoluble αSyn aggregates, and its circuit dysfunction may contribute to prevalent psychiatric deficits in PD. Yet, how αSyn aggregates affect the amygdala function remains elusive. In the present study, we examined the presence of αSyn in glutamatergic axon terminals and how its aggregation affects glutamatergic transmission in the basolateral amygdala (BLA). Using confocal microscopy, we showed that αSyn is primarily present in the axon terminals expressing vesicular glutamate transporter 1 (vGluT1), but not in those expressing vGluT2. Using electrophysiology and optogenetics, we found that glutamatergic neurotransmission from vGluT1+ axon terminals are functionally more vulnerable than vGluT2+ axon terminals to the toxic effects of pathological αSyn aggregation triggered by αSyn preformed fibrils (PFFs). Using the PFFs models and mouse genetics, we showed that loss of αSyn promotes short-term depression of cortico-BLA synapses responding to repetitive stimuli, leading to an input-selective filtering of cortical inputs to the BLA. Together, we demonstrate that αSyn expresses specifically in a subset of synapses in mouse amygdala, which causes an input-specific decrease of cortical inputs to the BLA as αSyn aggregation forms. These results might be relevant to the reduced cortical control of amygdala function that has been associated with psychiatric deficits in PD.
Competing Interest Statement
P.B. has consulted for Axial Therapeutics, Calico, CuraSen, Enterin Inc, Fujifilm-Cellular Dynamics Inc, Idorsia and Lundbeck A/S. He has received commercial support for research from Lundbeck A/S and Roche, and has ownership interests in Acousort AB, Axial Therapeutics, Enterin Inc. and RYNE Biotechnology Inc.
Footnotes
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Conflicts of interest P.B. has consulted for Axial Therapeutics, Calico, CuraSen, Enterin Inc, Fujifilm-Cellular Dynamics Inc, Idorsia and Lundbeck A/S. He has received commercial support for research from Lundbeck A/S and Roche, and has ownership interests in Acousort AB, Axial Therapeutics, Enterin Inc. and RYNE Biotechnology Inc.