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

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 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.

From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein

“…The difference in α-syn levels between the VGLUT1 positive terminals in amygdala and the VGLUT2 positive terminals in thalamus is further supported by reduced activity in cortico-amygdalal synapses in α-syn knockout mice [149]. Additionally, when α-syn aggregates, leaving a reduced amount of soluble α-syn, the transmission in VGLUT1 synapses in amygdala, but not the VGLUT2 synapses in thalamus, is reduced [149]. Although the general tendency is that more α-syn is present in VGLUT1 terminalis compared to VGLUT2 terminals, in some regions, like substantia nigra pars compacta, there are both α-syn positive and negative VGLUT1 synapses [150].…”

“…There is also a distinction in the amount of α-syn between the vesicular glutamate transporter 1 (VGLUT1) positive terminals and VGLUT2 positive terminals. In, e.g., mouse amygdala, where most of the glutamatergic neurons are VGLUT1 positive, there is much more α-syn than in the VGLUT2 positive glutamatergic neurons in the mouse thalamus [149]. The difference in α-syn levels between the VGLUT1 positive terminals in amygdala and the VGLUT2 positive terminals in thalamus is further supported by reduced activity in cortico-amygdalal synapses in α-syn knockout mice [149].…”

“…In, e.g., mouse amygdala, where most of the glutamatergic neurons are VGLUT1 positive, there is much more α-syn than in the VGLUT2 positive glutamatergic neurons in the mouse thalamus [149]. The difference in α-syn levels between the VGLUT1 positive terminals in amygdala and the VGLUT2 positive terminals in thalamus is further supported by reduced activity in cortico-amygdalal synapses in α-syn knockout mice [149]. Additionally, when α-syn aggregates, leaving a reduced amount of soluble α-syn, the transmission in VGLUT1 synapses in amygdala, but not the VGLUT2 synapses in thalamus, is reduced [149].…”

α-Synuclein propagation leads to synaptic abnormalities in the cortex through microglial synapse phagocytosis

“…Microglial engulfment may not be the sole cause of synapse degeneration during α-synuclein propagation. Other studies have suggested that PFF also impacts the formation and molecular organization of presynaptic terminals by inhibiting β-neurexin [ 34 ] or by decreasing the levels of soluble α-synuclein [ 35 ]. However, it is worth noting that the latter studies examined the direct effects of PFFs on neurons in culture, whereas our study assessed the effects of α-synuclein propagation throughout a neural network in an intact-tissue environment.…”

T Lymphocytes and Their Potential Role in Dementia with Lewy Bodies

“…Interestingly, CD3+ T cells were also identified in the hippocampus, near Lewy bodies and the excitatory presynaptic marker vesicular glutamate transporter 1 (vGLUT1) [ 50 ]. Previous studies have demonstrated co-localisation of α-syn and vGLUT1+ neurons in the hippocampus of C57BL/6N mice [ 51 , 52 ] and it has been proposed that vGLUT1+ neurons are vulnerable to α-syn pathology, resulting in detrimental effects on synaptic transmission [ 53 ]. Increased immunoreactivity for the pro-inflammatory cytokine interleukin 17A (IL-17A) has been detected in DLB/PDD brains [ 50 ], implying that Th17 cells that express this cytokine may contribute to neuronal damage.…”