Summary: A new study provides new insight into the molecular mechanisms that enable synaptic transmission critical for cognition.
Our cognitive abilities come down to how well the connections, or synapses, between our brain cells transmit signals. A new study by researchers at MIT's Picower Institute for Learning and Memory digs deep into the molecular mechanisms that enable synaptic transmission to show the distinct role of a protein that when mutated has been linked to causing intellectual disability.
The key protein, called SAP102, is one of four members of a family of proteins, called PSD-MAGUKs, that regulate the transport and placement of key receptors called AMPARs on the receiving end of a synapse. But how each member of the family works, for instance as the brain progresses through development to maturity, is not well understood. The new study in the Journal of Neurophysiology shows that SAP102 and other family members like PSD-95, work in different ways, a feature whose evolution may have contributed to the greater cognitive capacity of mammals and other vertebrates.
"Our results show that PSD-95 and SAP102 regulate synaptic AMPAR function differently," wrote the researchers including senior author Weifeng Xu, assistant professor in MIT department of Brain and Cognitive Sciences, and lead author Mingna Liu, a former postodoc in Xu's lab who is now at the University of Virginia.
"This study is part of a continuous effort in our lab to elucidate the molecular machinery for tuning synaptic transmission critical for cognition," Xu said.
In one key set of experiments in rats in a region of the brain called the hippocampus, the researchers showed that while knocking out PSD-95 causes a reduction in AMPAR current frequency and amplitude, they could restore those by replacing PSD-95 with a different form, PSD-95alpha, or with SAP102. They did these manipulations by using a virus to make the swap, a technique called molecular replacement that Xu has developed.
But the two proteins are not merely interchangeable. Compared to control neurons with normal PSD-95 or cells in which PSD-95 was replaced with PSD-95alpha, cells in which PSD-95 was replaced with SAP102 had different AMPAR current "kinetics," meaning that the currents took longer to decay. That timing difference made by SAP102 could make an important difference in how synapses operate to affect cognition.
In all the findings suggest that the diversity of AMPAR regulation leads to cognitively consequential differences in current timing at synapses. NeuroscienceNews.com image is in the public domain.
"These data showed that PSD-95alpha and SAP102 have distinct effects on the decay time of synaptic AMPAR currents, which potentially lead to differential synaptic integration for neuronal information processing," they wrote.
In another set of experiments, the team showed that SAP102 uniquely depends on another protein called CNIH-2. Knocking the protein down on its own didn't affect AMPAR currents, but when they knocked down CNIH-2 in the context of replacing PSD-95 with PSD-95alpha or SAP102, the researchers found that SAP102 could no longer restore the currents. Meanwhile, knocking down CNIH-2 had no effect on PSD-95alpha's rescue of AMPAR currents.
Funding: National Institutes of Health, MIT Simons Seed Grant funded this study.
Original Research: Abstract for "SAP102 regulates synaptic AMPAR function through a CNIH-2-dependent mechanism" by Mingna Liu, Rebecca Shi, Hongik Hwang, Kyung Seok Han, Man Ho Wong, Xiaobai Ren, Laura D. Lewis, Emery N. Brown, and Weifeng Xu in Journal of Neurophysiology. Published September 21 2018.
MIT"Protein Has Unique Effects in the Neural Connections Related to Information Processing." NeuroscienceNews. NeuroscienceNews, 9 October 2018.
MIT"Protein Has Unique Effects in the Neural Connections Related to Information Processing." http://neurosciencenews.com/protein-information-processing-9988/ (accessed October 9, 2018).
The postsynaptic density (PSD)-95-like, disk-large (DLG) membrane-associated guanylate kinase (PSD/DLG-MAGUK) family of proteins scaffold α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complexes to the postsynaptic compartment and are postulated to orchestrate activity-dependent modulation of synaptic AMPAR functions. SAP102 is a key member of this family, present from early development, before PSD-95 and PSD-93, and throughout life. Here we investigate the role of SAP102 in synaptic transmission using a cell-restricted molecular replacement strategy, where SAP102 is expressed against the background of acute knockdown of endogenous PSD-95. We show that SAP102 rescues the decrease of AMPAR-mediated evoked excitatory postsynaptic currents (AMPAR eEPSCs) and AMPAR miniature EPSC (AMPAR mEPSC) frequency caused by acute knockdown of PSD-95. Further analysis of the mini events revealed that PSD-95-to-SAP102 replacement but not direct manipulation of PSD-95 increases the AMPAR mEPSC decay time. SAP102-mediated rescue of AMPAR eEPSCs requires AMPAR auxiliary subunit cornichon-2, whereas cornichon-2 knockdown did not affect PSD-95-mediated regulation of AMPAR eEPSC. Combining these observations, our data elucidate that PSD-95 and SAP102 differentially influence basic synaptic properties and synaptic current kinetics potentially via different AMPAR auxiliary subunits.
Synaptic scaffold proteins postsynaptic density (PSD)-95-like, disk-large (DLG) membrane-associated guanylate kinase (PSD-MAGUKs) regulate synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function. However, the functional diversity among different PSD-MAGUKs remains to be categorized. We show that distinct from PSD-95, SAP102 increase the AMPAR synaptic current decay time, and the effect of SAP102 on synaptic AMPAR function requires the AMPAR auxiliary subunit cornichon-2. Our data suggest that PSD-MAGUKs target and modulate different AMPAR complexes to exert specific experience-dependent modification of the excitatory circuit.