MODULATION OF CHOLINERGIC SIGNAL TRANSMISSION BY REELIN: NOVEL APPROACHES TO NEURODEGENERATIVE DISEASES

The extracellular matrix protein reelin plays a crucial role in neuronal migration and brain lamination during embryonic development. In the mature brain, reelin is mainly expressed by inhibitory interneurons and modulates central neurophysiological processes, such as learning and memory, by modulating both excitatory glutamatergic and inhibitory GABAergic neuronal signaling. More recently, the investigation of reelin signaling has gained clinical relevance, as studies on humans suggest that a gain of function mutation in the reelin gene may mediate resilience to hereditary autosomal dominant Alzheimer’s disease (AD). Given that the dysfunction of cholinergic signaling is an important aspect of AD pathogenesis, we investigated the direct effect of Reelin on acetylcholine-induced calcium signals. Calcium imaging of primary hippocampal neurons and of the human neuronal cell line SH-SY5Y revealed that reelin modulates acetylcholine-induced calcium signals mainly via muscarinic acetylcholine receptors. A detailed analysis of the reelin signaling cascade suggests that this effect is mediated via a non-canonical reelin signaling pathway. Furthermore, reelin increases nuclear translocation of the transcription factor CREB, alters epigenetic protein modifications and modulates the proteome of the investigated neurons. Identifying the underlying molecular mechanisms of the reelin effect on the cholinergic system will not only complement our knowledge of reelin’s impact on neuronal signal transmission but may also contribute to a better understanding of the role of reelin in neurodegenerative diseases, such as AD.