Schematic view of the main synaptic pathways involved in intellectual disability (ID) highlighting common altered processes (in colored box as Endocytosis). Proteins mutated in ID are shown in italic bold underline (Ophn1) and the affected signaling pathways are shown in italic (Rho A/ROCK pathway). Arrows indicate a stimulating or an inhibitory effect, whereas the dashed lines indicate a potential effect. In the pre-synaptic compartment, ID-related proteins are involved in the regulation of different steps of synaptic vesicle traffic. Ophn1 (oligophrenin 1) inhibits the Rho A/ROCK pathway (in purple) that is involved in regulation of the actin cytoskeleton dynamic during endocytosis. The protein αGDI is involved in synaptic vesicle trafficking through regulation of Rab GTPase activities. Finally, IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) and its partner NCS-1 (neuronal calcium sensor-1) may regulate synaptic vesicles exocytosis through modulation of N-VGCC (N-type voltage-gated calcium channel) activity (light purple dashed line). In the post-synaptic compartment, ID-related proteins are involved in both actin cytoskeleton dynamic and membrane trafficking, and consequently in AMPA-receptor (AMPA R) trafficking. Various ID-related proteins, including Ophn1, αPIX, srGAP3, IQSEC2 and SynGAP regulate directly or indirectly (i.e., in the case of SynGAP and SAP102, through the Ras pathway) the Rho A/Rock pathway, the Rac/Cdc42 pathway or the Arf6 pathway, which control the actin cytoskeleton dynamic. IL1RAPL1 regulates c-Jun N-terminal kinases (JNK) pathway and thereby PSD-95 localization (light purple arrows), and possibly AMPA R trafficking (light purple dashed line). SAP102 and SynGAP also regulate AMPA R trafficking through control of the Ras/ERK pathway (orange line) as Ophn1 does through the control of Rho GTPase during endocytosis (purple line). For more information on this topic, please refer to the article by Pavlowsky et al. on pages 682–693.
This is a preview of subscription content, access via your institution