Data-driven Synapse Classification Reveals a Logic of Glutamate Receptor Diversity

Overview

Journal bioRxiv

Date 2024 Dec 23

PMID 39713368

Authors

Kristina D Micheva

Anish K Simhal

Jenna Schardt

Stephen J Smith

Richard J Weinberg

Scott F Owen

Affiliations

Soon will be listed here.

Abstract

The rich diversity of synapses facilitates the capacity of neural circuits to transmit, process and store information. We used multiplex super-resolution proteometric imaging through array tomography to define features of single synapses in mouse neocortex. We find that glutamatergic synapses cluster into subclasses that parallel the distinct biochemical and functional categories of receptor subunits: GluA1/4, GluA2/3 and GluN1/GluN2B. Two of these subclasses align with physiological expectations based on synaptic plasticity: large AMPAR-rich synapses may represent potentiated synapses, whereas small NMDAR-rich synapses suggest "silent" synapses. The NMDA receptor content of large synapses correlates with spine neck diameter, and thus the potential for coupling to the parent dendrite. Overall, ultrastructural features predict receptor content of synapses better than parent neuron identity does, suggesting synapse subclasses act as fundamental elements of neuronal circuits. No barriers prevent future generalization of this approach to other species, or to study of human disorders and therapeutics.

References

Kerchner G, Nicoll R . Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci. 2008; 9(11):813-25. PMC: 2819160. DOI: 10.1038/nrn2501. View

Emes R, Grant S . Evolution of synapse complexity and diversity. Annu Rev Neurosci. 2012; 35:111-31. DOI: 10.1146/annurev-neuro-062111-150433. View

Beaulieu-Laroche L, Toloza E, van der Goes M, Lafourcade M, Barnagian D, Williams Z . Enhanced Dendritic Compartmentalization in Human Cortical Neurons. Cell. 2018; 175(3):643-651.e14. PMC: 6197488. DOI: 10.1016/j.cell.2018.08.045. View

Kennedy M . Signal-processing machines at the postsynaptic density. Science. 2000; 290(5492):750-4. DOI: 10.1126/science.290.5492.750. View

Nicoll R, Schulman H . Synaptic memory and CaMKII. Physiol Rev. 2023; 103(4):2877-2925. PMC: 10642921. DOI: 10.1152/physrev.00034.2022. View

Fremaux N, Gerstner W . Neuromodulated Spike-Timing-Dependent Plasticity, and Theory of Three-Factor Learning Rules. Front Neural Circuits. 2016; 9:85. PMC: 4717313. DOI: 10.3389/fncir.2015.00085. View

Falkovich R, Danielson E, Perez de Arce K, Wamhoff E, Strother J, Lapteva A . A synaptic molecular dependency network in knockdown of autism- and schizophrenia-associated genes revealed by multiplexed imaging. Cell Rep. 2023; 42(5):112430. PMC: 10259678. DOI: 10.1016/j.celrep.2023.112430. View

Tovar K, McGinley M, Westbrook G . Triheteromeric NMDA receptors at hippocampal synapses. J Neurosci. 2013; 33(21):9150-60. PMC: 3755730. DOI: 10.1523/JNEUROSCI.0829-13.2013. View

Unterauer E, Boushehri S, Jevdokimenko K, Masullo L, Ganji M, Sograte-Idrissi S . Spatial proteomics in neurons at single-protein resolution. Cell. 2024; 187(7):1785-1800.e16. DOI: 10.1016/j.cell.2024.02.045. View

10.

Forrest D, Yuzaki M, Soares H, Ng L, Luk D, Sheng M . Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron. 1994; 13(2):325-38. DOI: 10.1016/0896-6273(94)90350-6. View

11.

Simhal A, Zuo Y, Perez M, Madison D, Sapiro G, Micheva K . Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome. Sci Rep. 2019; 9(1):13855. PMC: 6761194. DOI: 10.1038/s41598-019-50240-x. View

12.

Nimchinsky E, Yasuda R, Oertner T, Svoboda K . The number of glutamate receptors opened by synaptic stimulation in single hippocampal spines. J Neurosci. 2004; 24(8):2054-64. PMC: 6730404. DOI: 10.1523/JNEUROSCI.5066-03.2004. View

13.

Holderith N, Lorincz A, Katona G, Rozsa B, Kulik A, Watanabe M . Release probability of hippocampal glutamatergic terminals scales with the size of the active zone. Nat Neurosci. 2012; 15(7):988-97. PMC: 3386897. DOI: 10.1038/nn.3137. View

14.

Hodge R, Bakken T, Miller J, Smith K, Barkan E, Graybuck L . Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019; 573(7772):61-68. PMC: 6919571. DOI: 10.1038/s41586-019-1506-7. View

15.

Holderith N, Heredi J, Kis V, Nusser Z . A High-Resolution Method for Quantitative Molecular Analysis of Functionally Characterized Individual Synapses. Cell Rep. 2020; 32(4):107968. PMC: 7408500. DOI: 10.1016/j.celrep.2020.107968. View

16.

Nusser Z, Lujan R, Laube G, Roberts J, Molnar E, Somogyi P . Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron. 1998; 21(3):545-59. DOI: 10.1016/s0896-6273(00)80565-6. View

17.

Petralia R, Sans N, Wang Y, Wenthold R . Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol Cell Neurosci. 2005; 29(3):436-52. PMC: 1414063. DOI: 10.1016/j.mcn.2005.03.013. View

18.

Paoletti P, Bellone C, Zhou Q . NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013; 14(6):383-400. DOI: 10.1038/nrn3504. View

19.

Verhoog M, Obermayer J, Kortleven C, Wilbers R, Wester J, Baayen J . Layer-specific cholinergic control of human and mouse cortical synaptic plasticity. Nat Commun. 2016; 7:12826. PMC: 5025530. DOI: 10.1038/ncomms12826. View

20.

Micheva K, Smith S . Array tomography: a new tool for imaging the molecular architecture and ultrastructure of neural circuits. Neuron. 2007; 55(1):25-36. PMC: 2080672. DOI: 10.1016/j.neuron.2007.06.014. View