Summary: A new study illuminates the molecular mechanisms that shape synaptic transmission, a process essential for cognition.
Source: MIT.
Our cognitive abilities depend on how effectively synapses—the connections between neurons—transmit information. Researchers at MIT’s Picower Institute for Learning and Memory explored the molecular machinery that controls synaptic signaling and identified a distinct role for the protein SAP102, a mutation of which has been associated with intellectual disability.
The study focuses on a family of scaffold proteins known as PSD-MAGUKs, which arrange and regulate AMPA-type glutamate receptors (AMPARs) on the postsynaptic side of excitatory synapses. Although several MAGUK family members are present in the brain, how each contributes across development and into maturity has been unclear. The new work, published in the Journal of Neurophysiology, compares SAP102 with the better-known PSD-95 and reveals that these related scaffold proteins influence synaptic AMPAR function in different, functionally important ways. The authors suggest that this functional diversity may have evolved to support more complex information processing in vertebrates.
“Our results show that PSD-95 and SAP102 regulate synaptic AMPAR function differently,” the research team reports. The senior author is Weifeng Xu, assistant professor in MIT’s Department of Brain and Cognitive Sciences, and the lead author is Mingna Liu, formerly a postdoctoral researcher in Xu’s lab.
Distinct effects on synaptic current kinetics
The researchers performed targeted experiments in the rat hippocampus to test how different PSD-MAGUK proteins shape AMPAR-mediated currents. Using a molecular replacement technique developed in Xu’s lab, they acutely knocked down endogenous PSD-95 and replaced it with either an alternative form of PSD-95 (PSD-95alpha) or with SAP102, delivered by virus to the same cells.
Both PSD-95alpha and SAP102 were capable of restoring the reduction in AMPAR current frequency and amplitude that resulted from PSD-95 knockdown. However, SAP102 produced a clear and reproducible change in the kinetics of synaptic AMPAR currents: events decayed more slowly when PSD-95 was replaced by SAP102 than when cells retained normal PSD-95 or were replaced with PSD-95alpha. In other words, while several MAGUKs can support the presence and basic strength of AMPAR currents, SAP102 uniquely prolongs those currents’ decay time.
These timing differences are not trivial. The decay time of synaptic currents influences how inputs are integrated by a neuron, affects temporal summation, and can therefore alter the way information is encoded and processed across neural circuits. The authors emphasize that differential regulation of current kinetics by MAGUK family members may shape information processing in ways that contribute to cognition.
Dependence on an AMPAR auxiliary subunit
To dissect the molecular basis for these distinct effects, the team examined the role of cornichon-2 (CNIH-2), an auxiliary subunit that associates with AMPARs and modulates their function. They found that SAP102’s ability to rescue AMPAR currents after PSD-95 knockdown depended on the presence of CNIH-2: reducing CNIH-2 blocked SAP102’s rescue. By contrast, PSD-95alpha’s rescue of AMPAR currents was unaffected by CNIH-2 manipulation.
These results indicate that SAP102 and PSD-95alpha organize different AMPAR complexes—SAP102 appears to work together with CNIH-2-containing receptor assemblies, whereas PSD-95alpha does not require CNIH-2 for its effect. That divergence provides a plausible molecular explanation for the differences in current kinetics observed when SAP102 substitutes for PSD-95.
Taken together, the experiments show that PSD-95 and SAP102 can both support synaptic AMPAR function but do so via distinct molecular partnerships that lead to different temporal profiles of synaptic signaling. Such diversity among scaffold proteins likely contributes to how different cell types and circuits tune information encoding and integration.
Funding: National Institutes of Health, MIT Simons Seed Grant.
Source: David Orenstein – MIT.
Publisher: NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: “SAP102 regulates synaptic AMPAR function through a CNIH-2-dependent mechanism,” Journal of Neurophysiology. DOI: 10.1152/jn.00731.2017. Published September 21, 2018.
MIT. “Protein Has Unique Effects in the Neural Connections Related to Information Processing.” NeuroscienceNews, 9 October 2018.
Abstract (summary)
SAP102 regulates synaptic AMPAR function through a CNIH-2-dependent mechanism
PSD-MAGUK scaffold proteins organize AMPAR complexes at excitatory synapses and are thought to direct activity-dependent modulation of synaptic transmission. SAP102 is expressed early in development and persists into adulthood. Using cell-restricted molecular replacement after acute knockdown of endogenous PSD-95, the authors show that SAP102 rescues reductions in AMPAR-evoked and miniature excitatory postsynaptic currents caused by loss of PSD-95. Crucially, replacing PSD-95 with SAP102—but not altering PSD-95 directly—increases the decay time of AMPAR miniature events. SAP102’s rescue of evoked AMPAR currents requires the AMPAR auxiliary subunit cornichon-2, whereas PSD-95alpha’s regulation of AMPAR currents does not. These observations indicate that PSD-95 and SAP102 differentially influence basic synaptic properties and current kinetics, likely by targeting distinct AMPAR complexes.
Significance
This work demonstrates functional diversity among PSD-MAGUK scaffold proteins: SAP102 uniquely prolongs AMPAR current decay and relies on CNIH-2, suggesting that different MAGUKs target and modulate distinct AMPAR assemblies. Such molecular specialization provides a mechanism for specific, experience-dependent modification of excitatory circuits that underlies complex information processing.