Premium
Psychosis‐Like Behavior and Hyperdopaminergic Dysregulation in Human α ‐Synuclein BAC Transgenic Rats
Author(s) -
Polissidis Alexia,
Koronaiou Maria,
Kollia Vasia,
Koronaiou Effrosyni,
NakosBimpos Modestos,
Bogiongko Marios,
Vrettou Sofia,
Karali Katerina,
Casadei Nicolas,
Riess Olaf,
Sardi Sergio P.,
Xilouri Maria,
Stefanis Leonidas
Publication year - 2021
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.28383
Subject(s) - psychosis , neuroscience , neurodegeneration , phenotype , psychology , schizophrenia (object oriented programming) , dopamine , endophenotype , parkinson's disease , disease , medicine , biology , psychiatry , genetics , gene , cognition
Background Parkinson's disease psychosis is a prevalent yet underreported and understudied nonmotor manifestation of Parkinson's disease and, arguably, the most debilitating. It is unknown if α‐synuclein plays a role in psychosis, and if so, this endophenotype may be crucial for elucidating the neurodegenerative process. Objectives We sought to dissect the underlying neurobiology of novelty‐induced hyperactivity, reminiscent of psychosis‐like behavior, in human α‐synuclein BAC rats. Results Herein, we demonstrate a prodromal psychosis‐like phenotype, including late‐onset sensorimotor gating disruption, striatal hyperdopaminergic signaling, and persistent novelty‐induced hyperactivity (up to 18 months), albeit reduced baseline locomotor activity, that is augmented by d‐amphetamine and reversed by classical and atypical antipsychotics. MicroRNA‐mediated α‐synuclein downregulation in the ventral midbrain rescues the hyperactive phenotype and restores striatal dopamine levels. This phenotype is accompanied by an abundance of age‐, brain region– and gene dose–dependent aberrant α‐synuclein, including hyperphosphorylation, C‐terminal truncation, aggregation pathology, and mild nigral neurodegeneration (27%). Conclusions Our findings demonstrate a potential role of α‐synuclein in Parkinson's disease psychosis and provide evidence of region‐specific perturbations prior to neurodegeneration phenoconversion. The reported phenotype coincides with the latest clinical findings that suggest a premotor hyperdopaminergic state may occur, while at the same time, premotor psychotic symptoms are increasingly being recognized. © 2020 International Parkinson and Movement Disorder Society