Impaired Cortico-Amygdala Functional Connectivity Can Drive Social Behavior Deficits in Synucleinopathies
The small molecule protein alpha-synuclein forms insoluble aggregates in a group of neurological disorders, including Parkinsons disease and dementia with Lewy bodies, that are collectively called synucleinopathies. However, it remains poorly understood how the aggregated alpha-synuclein disrupts normal connectivity and function of complex neural circuits, prior to robust neurodegeneration, leading to the manifestation of various motor, emotion, and cognitive symptoms in synucleinopathies. In the present study, we combined electrophysiology, optogenetics, mouse model of synucleinopathies, and behavioral analysis to address this question. Using an alpha-synuclein preformed fibrils-based mouse model of synucleinopathies, we reported dynamic changes in the levels of alpha-synuclein pathology in the basolateral amygdala (BLA) circuits. Such dynamic changes associated with an accumulation of alpha-synuclein aggregates within cortical glutamatergic afferents to the BLA at an initial stage, followed by gradual loss of cortical inputs and BLA principal neurons at late stage. Moreover, we found that the cortical, but not the thalamic, afferents to the BLA showed functional impairments that were highly correlated with the manifestation of defected sociability in mice with alpha-synuclein pathology. Furthermore, we provided experimental evidence showing that the impaired social behavior of mice was rescued by chemogenetic stimulation of cortico-BLA inputs. Altogether, we presented a series of evidence to delineate key circuit events associated with alpha-synuclein pathology development in a complex neuronal network. The present work highlights the necessity of a thorough investigation of functional consequences of alpha-synuclein aggregation to advance our understand of pathophysiology of synucleinopathies and development of effective therapies.