α-Synuclein Oligomers Oppose Long-Term Potentiation and Impair Memory Through a Calcineurin-Dependent Mechanism: Relevance to Human Synucleopathic Diseases

J Neurochem. 2012 Feb;120(3):440-52. doi: 10.1111/j.1471-4159.2011.07576.x. Epub 2011 Nov 28.

Abstract

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 Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism
  • Analysis of Variance
  • Animals
  • Biophysics
  • Calcineurin / metabolism*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Disease Models, Animal
  • Drug Administration Routes
  • Electric Stimulation
  • Fear / drug effects
  • Female
  • Hippocampus / cytology
  • Humans
  • In Vitro Techniques
  • L-Lactate Dehydrogenase / metabolism
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • Male
  • Memory Disorders / chemically induced*
  • Memory Disorders / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neuroblastoma / pathology
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Transfection
  • alpha-Synuclein* / chemistry
  • alpha-Synuclein* / metabolism
  • alpha-Synuclein* / pharmacology

Substances

  • alpha-Synuclein
  • L-Lactate Dehydrogenase
  • Alkaline Phosphatase
  • Calcineurin
  • Calcium