Elucidating the molecular mechanisms by which mammalian Latrophilin Adhesion GPCRs function in synapse formation in vivo
Final Report Abstract
Latrophilins are uniquely structured proteins located in the cell membrane that are able to mediate adhesive forces between cells as well as transduce signals into the cell in response to cues from the environment. They play an essential role in the development of the nervous system, in particular during the formation of neuronal connections (synapses). Defects in the genes encoding Latrophilins are related to various neurological and psychiatric disorders, for example intellectual impairment, epilepsy, Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). A major contributing factor to some of these disorders is an imbalance between neuronal activation (mediated by excitatory synapses) and inhibition (mediated by inhibitory synapses). Humans and rodents harbour three forms of Latrophilins (Lphn1, Lphn2, Lphn3). Lphn2 and Lphn3 have well-understood functions in the formation of excitatory synapses. However, unlike its related molecules, the role of Lphn1 has been unclear due to contradicting findings in previous studies. The first major result of this project was that Lphn1, unlike other Latrophilins, is not essential for excitatory synapse assembly, but is required for the formation of inhibitory synaptic connections. Neurons lacking Lphn1 were inhibited ~50% less efficiently than the respective controls, suggesting a major role of Lphn1 in maintaining the balance between excitation and inhibition in the brain. Moreover, STED super-resolution microscopy was used to demonstrate the precise localization of Latrophilins in neurons. Intriguingly, Latrophilins are not uniformly distributed, but rather form clusters of ~80-90 nanometers within synapses. Such nanostructures could act as signalling hubs, in which Latrophilins cluster together to regulate synapse formation. Indeed, this project contributed to an investigation unravelling a molecular mechanism by which Latrophilins are clustered on one side of the synapse (postsynaptic side) by their interaction partners located on the opposing side (presynaptic side), which leads to the assembly of specialized synaptic protein complexes on both sides. This suggests that Latrophilins are at the center of synaptic protein supercomplexes that initiate the formation of new connections between neurons. This project has not only enhanced our understanding on how Latrophilins are able to initiate neuronal connections on a molecular level, but has shown that different Latrophilins can mediate the formation of fundamentally opposed types of synapses. These findings lay the groundwork to understand pathologies associated with Latrophilin dysfunction and possibly facilitate pharmacological developments directed at such disorders.
Publications
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Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses. The Journal of Neuroscience, 44(23), e1978232024.
Mat, Daniel; Lopez, Jaybree M.; Sando, Richard C. & Sdhof, Thomas C.
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“Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses.”, Gordon Research Seminar on Molecular and Cellular Neurobiology (05/2024), Lucca, Italy
Daniel Matúš
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Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes. Science, 387(6731), 322-329.
Zhang, Xuchen; Chen, Xudong; Matúš, Daniel & Südhof, Thomas C.
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“A molecular code of synapse specificity orchestrated by Adhesion GPCRs”, SFB1423 lecture (01/2025), Leipzig, Germany
Daniel Matúš
