br Functional organization of postsynaptic glutamate

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 Azacyclonol 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.
Acknowledgements We would like to thank Dr. Thomas Blanpied, Sai Sachin Divakaruni, Dr. Helmut Kessels, Feline Lindhout, Dieudonnée van de Willige, and all members of the MacGillavry lab for discussions and critical reading of the manuscript. This work was supported by NWO (ALW-VENI 863.13.020, ALW-VIDI 171.029 and the Graduate Program of Quantitative Biology and Computational Life Sciences), the European Research Council (ERC-StG 716011), and a NARSAD Young Investigator Award (24995).
Introduction Schizophrenia has three major symptoms: positive, negative, and cognitive (Labrie et al., 2008, Weiner, 2003). Previous studies on the positive symptoms of schizophrenia often used the latent inhibition model (Gray et al., 1995). They also predominantly investigated the involvement of the mesocorticolimbic dopamine system, suggesting that the dopamine system is involved in the positive symptoms of schizophrenia (Feldon and Weiner, 1992, Gray et al., 1997). Some studies reported that the glutamate system also plays a crucial role in latent inhibition, representing the negative and cognitive symptoms of schizophrenia (Weiner and Arad, 2009). Latent inhibition appears to be an important model for assessing the symptoms of schizophrenia.