ABSTRACT
Phosphatidylinositol 4-phosphate (PI4P) is a low abundant phospholipid with important roles in lipid transport and membrane trafficking. However, little is known of its metabolism and function in neurons. Here, we investigate its subcellular distribution and functional roles in dendrites of rodent hippocampal neurons during resting state and long-term synaptic potentiation (LTP). We show that neural activity causes dynamic reversible changes in PI4P metabolism in dendrites. Upon LTP induction, PI4KIIIα, a type III phosphatidylinositol 4-kinase, localizes to the dendritic plasma membrane (PM) in a calcium-dependent manner and causes substantial increase in the levels of PI4P. Acute inhibition of PI4KIIIα activity abolishes trafficking of the AMPA-type glutamate receptor to the PM during LTP induction, and silencing of PI4KIIIα expression in the hippocampal CA1 region causes severe impairment of LTP and long-term memory. Collectively, our results identify an essential role for PI4KIIIα-dependent PI4P synthesis in synaptic plasticity of central nervous system neurons.
Subject(s)
1-Phosphatidylinositol 4-Kinase , Long-Term Potentiation , 1-Phosphatidylinositol 4-Kinase/metabolism , CA1 Region, Hippocampal/metabolism , Hippocampus/metabolism , Receptors, AMPA/metabolism , Synapses/metabolismABSTRACT
Long-term potentiation (LTP) has long been considered as an important cellular mechanism for learning and memory. LTP expression involves NMDA receptor-dependent synaptic insertion of AMPA receptors (AMPARs). However, how AMPARs are recruited and anchored at the postsynaptic membrane during LTP remains largely unknown. In this study, using CRISPR/Cas9 to delete the endogenous AMPARs and replace them with the mutant forms in single neurons, we have found that the amino-terminal domain (ATD) of GluA1 is required for LTP maintenance. Moreover, we show that GluA1 ATD directly interacts with the cell adhesion molecule neuroplastin-65 (Np65). Neurons lacking Np65 exhibit severely impaired LTP maintenance, and Np65 deletion prevents GluA1 from rescuing LTP in AMPARs-deleted neurons. Thus, our study reveals an essential role for GluA1/Np65 binding in anchoring AMPARs at the postsynaptic membrane during LTP.
Subject(s)
Excitatory Postsynaptic Potentials/genetics , Long-Term Potentiation/genetics , Membrane Glycoproteins/genetics , Pyramidal Cells/metabolism , Receptors, AMPA/genetics , Animals , Embryo, Mammalian , Female , Gene Expression Regulation , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , HEK293 Cells , Hippocampus/cytology , Hippocampus/metabolism , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Membrane Glycoproteins/metabolism , Mice , Primary Cell Culture , Protein Domains , Pyramidal Cells/cytology , Receptors, AMPA/metabolism , Single-Cell Analysis , Synapses , Red Fluorescent ProteinABSTRACT
OBJECTIVE: To evaluate the method to correct the seconary nasolabial deformities after the surgical treatment in the patients with bilateral cleft lip. METHODS: From January 2000 to June 2003, forty patients with secondary deformities following repair of bilateral cleft lip were treated with a combined treatment procedures. AU of the forty cases underwent the following preoperative treatments: alveolar bone graft in 28 cases, preoperative orthodontics in 22 cases, prosthodontics in 20 cases and orthognathic surgery or distraction osteogenesis treatment in 20 cases, respectively. In order to improve the enlongation of nasal column, reconstruction of Cupid's bow, philtrum and correction procedures, continuous incision was made from the vermilion in median of the upper lip, the scar edge, the bilateral sides of the nasal column to the inner side of the nose, even extending the bilateral incision to nasolabial groove and nostril fundus. RESULTS: Forty patients were got the follow-ups for 3 months to 3.5 years and the satisfactory rate reached 95%. CONCLUSION: It is natural to emphasize the setting up of odontomaxillary frame and then utilize the surgical procedure to correct the secondary nasolabial parenchyma deformities. The method could be feasible and reliable for the correction of the secondary nasolabial parenchyma deformities after bilateral cleft lip repair.
