Abstract:
Synaptic plasticity is the physical locus of memory formation in the brain. Long-term potentiation (LTP) and long-term depression (LTD) are processes of long-lasting increase and decrease in synaptic strength respectively. Ca2+ ions enter through NMDA receptors, where they bind to Calmodulin (CaM). Ca2+-bound CaM, a limited resource, then binds to other proteins and is responsible for LTP and LTD depending on binding affinities and tuning mechanisms, thereby triggering plasticity. There is a consensus that activation of kinases like Calcium/calmodulin-dependent protein kinase II (CaMKII) induce LTP, while phosphatases like Calcineurin (CaN) induce LTD. However, recent studies have pointed out that a dynamic competition for CaM determines the precise balance of activated proteins. We attempted to develop a detailed downstream model of plasticity that accounts for the competitive binding of Ca2+-bound CaM and its effect on plasticity depending on realistic activity. Neurogranin (Ng), one of the key CaM-binding proteins, is known to preferentially influence plasticity by impeding the binding of CaN to Ca2+-bound CaM, thereby inhibiting LTD and enhancing LTP. This protein is the focus of our study. Most of the existing models explain experimental observations exploring synaptic plasticity. However, they do not include all downstream signalling pathways that are clearly known to change the long-term plasticity response of the synapse. We attempted to develop a biophysical model of long-term plasticity that accounts for modulatory changes in plasticity driven by the competitive binding of Ca2+-bound CaM that could explain the asymmetric influence of Ng and extend the existing models to include downstream signalling mechanisms. One of the most critical symptoms of Alzheimer's Disease (AD) is memory loss. Cellular investigations in AD synapses have shown an extended and a more pronounced LTD region, the mechanistic implications of which can be rooted to Ng due to its preferential influence triggering an impediment to LTD. Ng has been known to leak out from the hippocampal cytosol in AD synapses. As a result of decreased hippocampal Ng levels due to AD-related pathologies, the plasticity profile changes. Investigating these changes may help us build novel insights into memory formation and its disruption in AD.
