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

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    Evaluation Summary:

    The manuscript by Nagaraja et al. examines the synapse-specificity of alpha-synuclein aggregation and corresponding circuit dysfunction in the amygdala. Using confocal microscopy and slice electrophysiology, along with alpha-synuclein knockout mice and preformed fibrils, the authors demonstrate that cortico-amygdala, but not thalamo-amygdala, inputs are more vulnerable to alpha-synuclein aggregation and corresponding synaptic dysfunction. This has important implications for the etiology of psychiatric deficits that are common in Parkinson's disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

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

    Reviewer #1 (Public Review):

    Psychiatric symptoms in Parkinson's disease are debilitating, but there are few treatments that effectively reduce these symptoms long-term. The mechanisms that cause psychiatric symptoms in Parkinson's disease are unknown. However, it has been known for decades that abnormal alpha-synuclein is found in the amygdala, a brain region important for the control of emotions. Nagaraj et. al. present an article in which they attempt to characterize the differences in α-synuclein colocalization with vGluT1+ compared to vGluT2+ terminals in the BLA of a PFF mouse model. They successfully demonstrate convincing data that points to the preferential association of α-synuclein with vGluT1+ puncta and not vGluT2+ puncta. The authors also demonstrate that PFFs promote short-term depression of cortico-BLA …

  2. Evaluation Summary:

    The manuscript by Nagaraja et al. examines the synapse-specificity of alpha-synuclein aggregation and corresponding circuit dysfunction in the amygdala. Using confocal microscopy and slice electrophysiology, along with alpha-synuclein knockout mice and preformed fibrils, the authors demonstrate that cortico-amygdala, but not thalamo-amygdala, inputs are more vulnerable to alpha-synuclein aggregation and corresponding synaptic dysfunction. This has important implications for the etiology of psychiatric deficits that are common in Parkinson's disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  3. Reviewer #1 (Public Review):

    Psychiatric symptoms in Parkinson's disease are debilitating, but there are few treatments that effectively reduce these symptoms long-term. The mechanisms that cause psychiatric symptoms in Parkinson's disease are unknown. However, it has been known for decades that abnormal alpha-synuclein is found in the amygdala, a brain region important for the control of emotions. Nagaraj et. al. present an article in which they attempt to characterize the differences in α-synuclein colocalization with vGluT1+ compared to vGluT2+ terminals in the BLA of a PFF mouse model. They successfully demonstrate convincing data that points to the preferential association of α-synuclein with vGluT1+ puncta and not vGluT2+ puncta. The authors also demonstrate that PFFs promote short-term depression of cortico-BLA synapses in …

  4. Reviewer #2 (Public Review):

    The data presented are clear and of high quality. The conclusion that alpha-synuclein aggregation and corresponding synaptic dysfunction preferentially occurs in vGluT1 expressing cortical inputs (as opposed to vGluT2 expressing thalamic inputs) to the BLA is convincing, but a few additional clarifications and experiments would greatly help describe the mechanism of synapse dysfunction. Overall this manuscript provides helpful insight into the circuit dysfunctions that may contribute to non-motor psychiatric symptoms that commonly occur in Parkinson's disease.

    1. The BLA is a relatively large structure, and the labeled terminal fields of cortical and thalamic inputs (figure 2) don't show matching patterns. It would be helpful to clarify where in the BLA recordings were made (and where high mag images in …

  5. Reviewer #3 (Public Review):

    In this manuscript, the authors try to address whether glutamatergic axonal terminals are differentially impacted by a-syn aggregation, a key pathology seen in Parkinson's disease. Using a-syn PFF injection, and a-syn KO mice, the authors show a few interesting findings: 1. After a-syn PFF injection in the BLA, the strength of the cortical inputs was selectively reduced, while leaving thalamic inputs unaffected. 2. There is an interesting parallel finding on the release probability of cortical glutamatergic synaptic transmission after a-syn PFF injection and in the a-syn KO mice. The key findings are interesting, showing selective vulnerability of glutamatergic synapses, in which vGluT1+ terminals are more profoundly affected by a-syn PFF or loss of function.

    However, mechanistically, the authors implied …