A potential role of NMDA receptor-dependent expression of Striatin-4 in dendritic spine maturation

Abstract

Most excitatory synapses are located in dendritic spines of the postsynaptic neuron. Immatures spines, such as stubby spines or filopodia, do not possess a distinct spine head, while mature spines appear as mushroom-shaped with large heads, or thin spines with elongated necks and small heads. Spine maturation requires local dendritic protein synthesis in response to synaptic activity. Dysregulated mRNA trafficking and local protein synthesis can lead to altered spine morphology in neurodevelopmental disorders such as Fragile-X syndrome and autism. Nonetheless, the molecular mechanism underlying activity-dependent spine maturation is not fully understood. Striatin-4 (Zinedin) was identified in transcriptomic studies as an mRNA transcript present in hippocampal neuropil and a putative cargo of the RNA-binding protein FMRP. Interestingly, certain striatin-interacting proteins, namely mammalian STE20-like protein kinase 3 (MST3) and cortactin-binding protein 2 (CTTNBP2), are encoded by autism risk genes. Despite previous studies demonstrating Striatin-4 enrichment in dendritic spines, the function of Striatin-4 in neuron remains unknown. Here we found that Striatin-4 mRNA and protein expression in cortical and hippocampal neurons was regulated by neuronal activity and NMDA receptors. Notably, Striatin-4 was preferentially expressed in mature dendritic spines, and blockade of NMDA receptor by APV led to reduced Striatin-4 expression and a concomitant switch of mature spines to the immature stubby spines and filopodia. Striatin-4 knockdown in hippocampal neurons by shRNA also led to mature spines loss and increased proportions of the stubby spines and filopodia. These findings suggest that NMDA receptor-dependent synthesis of striatin-4 is crucial for dendritic spine maturation. This study was supported in part by the Research Grant Council of Hong Kong [General Research Fund (GRF) 16100814 and Early Career Scheme (ECS) 27119715].