The Effect of Scaffolding Proteins and Receptor Subunits on Synaptic Plasticity

Synaptic plasticity allows for communication between neurons, changing depending upon their level of activation. Plasticity occurs from the changing amount of neurotransmitter receptors located at the synapse, making the molecular mechanisms behind the fluctuating receptor frequency an interesting topic of research. This phenomenon is paramount to understanding learning and memory. Delgado et. al. recently demonstrated the role of post-synaptic density protein 95 in synaptic plasticity and excitatory development in "Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses." 

It was found that PSD-95, a scaffolding protein, enriches AMPA and NMDA receptor types in the post-synaptic membrane. PSD-95 has multiple functions, including its role in scaffolding and in organizing signaling cascades downstream of NMDA receptors and the development of excitatory synapses. The loss of PSD-95 follows NMDAR activation and Delgado et. al. demonstrated that the regulation of PSD-95 in the post-synaptic membrane is by Pin1. Pin1 blocks palmitoylation of PSD-95, which corresponded with decreased PSD-95 in post-synaptic dendrites and a reduced amount of excitatory synapses and associated dendritic spines, supporting the hypothesis of Pin1's role of binding to phosphorylated PSD-95 and regulating the accumulation of PSD-95 in hippocampal neurons. 

There are other studies investigating the process of synaptic rearrangements as well, but Kehoe et. al. investigates how the development and maintenance of synapses and their associated dendritic spines is regulated by changes in the NMDA receptors themselves. Specifically, it was found that the subunit GluN3A in NMDA receptors plays a roles as a "molecular brake" in synaptic maturation, as demonstrated in "GluN3A Promotes Dendritic Spine Pruning and Destabilization during Postnatal Development." Overexpressing GluN3A was shown to reduce dendritic spine density and decreased spine stability, and conversely, silencing GluN3A promoted dendritic spines while increasing stability. GluN3A of the NMDAR promoted spine elimination by limiting activity-dependent stabilization. Additionally, Kehoe et. al. found the expression of GluN3A was preferentially during periods postnatally of high structural plasticity, indicating its role as a brake preventing a premature stabilization of neuronal networks.

There are many aspects to the mechanisms behind synaptic plasticity. Investigating the relationship between the receptors and proteins involved in modulating the signaling is necessary to understanding how synapses are developed, regulated, and maintained. Since it has been discovered that both PSD-95 and GluN3A are associated with reduced dendritic spines of the synapse, I would be interested in future studies investigating the potential relationship between that scaffolding protein and the GluN3A region of the NMDA receptor, specifically. 

References:

1. Kehoe, L.A., Bellone, C., De Roo, M., Zandueta, A., Dey, P.N., Pérez-Otaño, I., and Muller, D. (2014). GluN3A Promotes Dendritic Spine Pruning and Destabilization during Postnatal Development. The Journal of Neuroscience. 34(28):9213–9221. https://doi.org/10.1523/JNEUROSCI.5183-13.2014 

2. Delgado, J.Y., Nall, D., and Selvin, P.R. (2020). Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses. Frontiers in Molecular Neuroscience. 13(10): 1-16. https://doi.org/10.3389/fnmol.2020.00010