α-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases

J. Neurochem. (2012) 120, 440–452. Intracellular deposition of fibrillar aggregates of α‐synuclein (αSyn) characterizes neurodegenerative diseases such as Parkinson’s disease (PD) and dementia with Lewy bodies. However, recent evidence indicates that small αSyn oligomeric aggregates that precede fibril formation may be the most neurotoxic species and can be found extracellularly. This new evidence has changed the view of pathological αSyn aggregation from a self‐contained cellular phenomenon to an extracellular event and prompted investigation of the putative effects of extracellular αSyn oligomers. In this study, we report that extracellular application of αSyn oligomers detrimentally impacts neuronal welfare and memory function. We found that oligomeric αSyn increased intracellular Ca2+ levels, induced calcineurin (CaN) activity, decreased cAMP response element‐binding protein (CREB) transcriptional activity and resulted in calcineurin‐dependent death of human neuroblastoma cells. Similarly, CaN induction and CREB inhibition were observed when αSyn oligomers were applied to organotypic brain slices, which opposed hippocampal long‐term potentiation. Furthermore, αSyn oligomers induced CaN, inhibited CREB and evoked memory impairments in mice that received acute intracerebroventricular injections. Notably, all these events were reversed by pharmacological inhibition of CaN. Moreover, we found decreased active CaN and reduced levels of phosphorylated CREB in autopsy brain tissue from patients affected by dementia with Lewy bodies, which is characterized by deposition of αSyn aggregates and progressive cognitive decline. These results indicate that exogenously applied αSyn oligomers impact neuronal function and produce memory deficits through mechanisms that involve CaN activation. Reversing the cognitive effects of the Parkinson's disease protein alpha synucleinThe present study was performed to investigate neuronal and behavioral effects elicited by small aggregates (oligomers) of α‐synuclein, the toxic protein present in the brain of patients affected by severe neurological disorders such as Parkinson’s disease and dementia with Lewy bodies. We found that extracellularly delivered α‐synuclein oligomers profoundly affect neuronal function and induce acute memory deficits that occurred independently of neuronal death and that could be reversed by inhibiting a specific neuronal enzyme. Notably, evidence of such an effect could be also observed in actual dise