title: Lithium increases synaptic GluA2 in hippocampal neurons by elevating the δ-catenin protein.
abstract: Lithium (Li+) is a drug widely employed for treating bipolar disorder, however the mechanism of action is not known. Here we study the effects of Li+in cultured hippocampal neurons on a synaptic complex consisting of δ-catenin, a protein associated with cadherins whose mutation is linked to autism, and GRIP, an AMPA receptor (AMPAR) scaffolding protein, and the AMPAR subunit, GluA2. We show that Li+elevates the level of δ-catenin in cultured neurons. δ-catenin binds to the ABP and GRIP proteins, which are synaptic scaffolds for GluA2. We show that Li+increases the levels of GRIP and GluA2, consistent with Li+-induced elevation of δ-catenin. Using GluA2 mutants, we show that the increase in surface level of GluA2 requires GluA2 interaction with GRIP. The amplitude but not the frequency of mEPSCs was also increased by Li+in cultured hippocampal neurons, confirming a functional effect and consistent with AMPAR stabilization at synapses. Furthermore, animals fed with Li+show elevated synaptic levels of δ-catenin, GRIP, and GluA2 in the hippocampus, also consistent with the findings in cultured neurons. This work supports a model in which Li+stabilizes δ-catenin, thus elevating a complex consisting of δ-catenin, GRIP and AMPARs in synapses of hippocampal neurons. Thus, the work suggests a mechanism by which Li+can alter brain synaptic function that may be relevant to its pharmacologic action in treatment of neurological disease.
authors: Department of Biochemistry and Molecular Pharmacology, New York University, Langone Medical Center, NY 10016, United States.
authors: Mobeen
authors: M
authors: Farooq
authors: Department of Biochemistry and Molecular Pharmacology, New York University, Langone Medical Center, NY 10016, United States.
authors: Seonil
authors: S
authors: Kim
authors: Department of Biochemistry and Molecular Pharmacology, New York University, Langone Medical Center, NY 10016, United States.
authors: Sunny
authors: S
authors: Patel
authors: Department of Biochemistry and Molecular Pharmacology, New York University, Langone Medical Center, NY 10016, United States.
authors: Latika
authors: L
authors: Khatri
authors: Department of Neuroscience and Physiology, New York University, Langone Medical Center, NY 10016, United States.
authors: Takuya
authors: T
authors: Hikima
authors: Department of Neuroscience and Physiology, New York University, Langone Medical Center, NY 10016, United States.
authors: Margaret E
authors: ME
authors: Rice
authors: Department of Biochemistry and Molecular Pharmacology, New York University, Langone Medical Center, NY 10016, United States. Electronic address: edward.ziff@nyumc.org.
authors: Edward B
authors: EB
authors: Ziff
mesh_terms: D000818:Animals; D051177:Catenins / Q000096:biosynthesis*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000096:biosynthesis*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D018091:Receptors, AMPA; D008094:Lithium; C104722:glutamate receptor ionotropic, AMPA 2; D000095002:Delta Catenin
keywords: AMPA receptor; GRIP; GluA2; Lithium; PICK1; δ-Catenin