br Conclusion br Acknowledgements br Introduction Synapses a

Conclusion
Acknowledgements
Introduction Synapses are the fundamental elements of neuronal networks that enable the processing, encoding, and retrieval of information in the brain, and pathological disruptions in synapse structure are broadly held to underlie the development of neurological disorders such as autism and schizophrenia (Volk et al., 2015). To maintain and adjust the efficiency of synaptic signaling, synapses are built from a broad array of components that assemble into large macromolecular machineries. At the presynaptic terminal, action potentials trigger the fast release of synaptic vesicles. Synaptic vesicles are docked at the active zone and primed for iCRT 14 australia by protein complexes containing e.g. Rab3-interacting molecules (RIM) and soluble N-ethylmaleimide-sensitive factor activating protein receptors (SNARE) (Sudhof, 2012). The release of glutamate is closely aligned with the postsynaptic receptors that are stably anchored in the opposing postsynaptic density (PSD), a complex molecular machine containing a plethora of scaffolding proteins and signaling molecules (Okabe, 2007; Sheng and Hoogenraad, 2007). How are these molecular complexes organized and precisely positioned to sustain synaptic transmission? In this review we will focus particularly on the functional distribution of glutamate receptors at the postsynaptic membrane.
Functional organization of postsynaptic glutamate receptors
Downstream effects of glutamate receptor positioning
Mechanisms underlying the subsynaptic positioning of glutamate receptors
Conclusions and future prospects The molecular organization of synapses is undoubtedly a critical determinant of the efficiency of synaptic transmission. The complexity of synapse organization has indeed been underlined by extensive genetic and biochemical approaches that over the past decades have resulted in a comprehensive “parts list” of synapses. Yet, how are these components properly assembled into the large macromolecular complexes that organize the glutamate receptors at the surface? Emerging evidence demonstrates that the structure and molecular organization of synapses is highly heterogeneous and organized in distinct subsynaptic nanodomains (Biederer et al., 2017), but we are only starting to understand how, within individual synapses, different proteins find their correct location. Undoubtedly, the overall assembly of synapses is directed by specific protein-protein interactions via well-defined protein interaction motifs (Kim and Sheng, 2004). These core biochemical processes give rise to the stable molecular complexes that effectively concentrate receptors at synaptic sites and couple these receptors to intracellular scaffolding, adaptor, and signaling proteins. At the same time, these mechanisms enable the dynamic modifications of synaptic structure in response to activity. However, while these mechanisms can explain the assembly and stoichiometry of specific components into molecular complexes, to date it is not fully understood how these mechanisms contribute to the spatial organization of molecules at the synapse, i.e. how proteins are positioned relative to each other within individual synapses. Moreover, apart from these classic biochemical operations, the contribution of biophysical processes such as steric hindrance, membrane composition (Tulodziecka et al., 2016), and phase transitions (Zeng et al., 2016) are only beginning to be explored in the context of synapse organization. Alterations in glutamatergic synapse structure and function seem to represent a common hallmark of many cognitive disorders (Volk et al., 2015). Intriguingly, these disorders span a broad clinical spectrum, including intellectual disability, autism spectrum disorder, and schizophrenia, but all seem to stem from a common defect; synaptic dysfunction. Indeed, these disorders are frequently associated with loss of synapses, or changes in morphology of dendritic spines. Given that many disease-associated genes are components of the glutamate receptor-associated complexes or can regulate glutamate receptor function through the actin cytoskeleton, indicates that disruptions in the precise positioning of glutamate receptors can underlie the development of these diseases. Future directions aimed at understanding the spatial organization of glutamate receptors will therefore not only be indispensable for a deeper insight in the regulation of synaptic transmission and plasticity, but will also contribute to the identification of disease mechanisms.