Venue: Centre Broca
Deepak Nair
Center for Neuroscience, Indian Institute of Science, Bangalore, India
Invited by Eric Hosy and Jean-Baptiste Sibarita (IINS)
Title
Structured lattice organization of nanoscale molecular condensates govern information transfer at single synapses
Abstract
In neuroscience, a significant challenge is understanding how the human brain stores knowledge and makes informed decisions across various spatial scales. This involves the brain’s ability to gather and organize information, construct mental models, and navigate uncertainty through probabilistic inference. Synapses, critical for brain communication, rely on precise protein arrangements to ensure efficient information transmission. However, the mechanisms behind synaptic information representation, especially at the finest scale of information processing in the brain, remain elusive. To address this challenge, we employ nanoscale imaging techniques to investigate the organization of key synaptic proteins crucial for successful synaptic transmission. Leveraging advanced technologies such as Single Molecule and Ensemble Super Resolution Microscopy, multivariate statistics, and molecular modeling, we evaluate alterations in thermodynamic signatures, distribution in synaptic functional zones, and nanoscale biochemical maps that emerge within single synapses. In the last decade our lab and others have accumulated compelling evidence confirming that signal processing at synapses is regulated using nanoscale machinery, which can assemble at the postsynaptic membrane and is at least 5-10 times smaller than the synaptic area itself. We present new insights in to the nanoscale distribution of critical synaptic markers, including Bassoon and Voltage-Gated Calcium Channels (VGCCs) at the active zone, as well as the AMPA receptor subunit at the postsynaptic density (Netrakanti et al, unpublished). From the molecular localization and the heterogeneity in their distribution within synapses, we extract molecular fingerprints contributing to the different outcomes observed in young and mature neurons during homeostatic scaling, a process integral to information processing diversity. These findings provide persuasive evidence that nanodomains result from the condensation of VGCCs and receptors, either independently or in association with scaffolding molecules, following the principles of liquid-liquid phase separation (Rajeev et al, 2022; Dhingra et al, unpublished). In summary, our research emphasizes that the regulation of release events at synapses is a multifaceted process influenced by the coordinated spatial arrangement of molecules at the nanoscale within the active zone and postsynaptic density. Additionally, our data suggests that differential nanoscale organization plays a pivotal role in the probabilistic inference of signals, influencing the properties of miniature excitatory postsynaptic currents (mEPSCs), which result from the random fusion of synaptic vesicles. In essence, to the best of our knowledge, for the first time we integrate the concepts of representing uncertainty, probabilistic inference, and the nanoscale spatial organization of these molecules as reference frames under a single framework to construct a comprehensive model of the synapse as a nanoscale information processing machine (Netrakanti et al (unpublished), Dhingra et al (unpublished).