Biology subjects

Khatri, L.

Publications and source records attributed to Khatri, L..

3 recordsLinked to original sources

bioRxiv2022

Ketamines rapid antidepressant effects are mediated by Ca2+ - permeable AMPA receptors in the hippocampus

Ketamine is shown to enhance excitatory synaptic drive in the hippocampus, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamines therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that inhibits excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment for one hour in cultured mouse hippocampal neurons significantly reduces calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately induces the expression of Ca2+- Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). Such ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and synaptic plasticity in cultured hippocampal neurons. When a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within one hour after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamines effects on animals behavior. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity in the hippocampus, which in turn enhances synaptic strength to induce rapid antidepressant actions.

neuroscience↗

bioRxiv2022

Optopharmacological tools for precise spatiotemporal control of oxytocin signaling in the central nervous system and periphery

Oxytocin is a neuropeptide critical for maternal physiology and social behavior, and is thought to be dysregulated in several neuropsychiatric disorders. Despite the biological and neurocognitive importance of oxytocin signaling, methods are lacking to activate oxytocin receptors with high spatiotemporal precision in the brain and peripheral mammalian tissues. Here we developed and validated caged analogs of oxytocin which are functionally inert until cage release is triggered by ultraviolet light. We examined how focal versus global oxytocin application affected oxytocin-driven Ca2+ wave propagation in mouse mammary tissue. We also validated the application of caged oxytocin in the hippocampus and auditory cortex with electrophysiological recordings in vitro, and demonstrated that oxytocin uncaging can accelerate the onset of mouse maternal behavior in vivo. Together, these results demonstrate that optopharmacological control of caged peptides is a robust tool with spatiotemporal precision for modulating neuropeptide signaling throughout the brain and body.

neuroscience↗

bioRxiv2020

Phosphorylation of AMPA receptor subunit GluA1 regulates clathrin-mediated receptor endocytosis

Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. In particular, during long-term potentiation and synaptic up-scaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to activity-dependent phosphorylation of AMPAR subunit GluA1, and subsequent increases in GluA1 surface expression, which can be achieved by either an increase in exocytosis or a decrease in endocytosis of the receptors. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we first employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 Serine 845 (S845) plays a more important role in receptor endocytosis than exocytosis during synaptic plasticity. Notably, endocytosis of AMPARs depends upon the clathrin adaptor, AP2, which recruits cargo proteins into endocytic clathrin coated pits. Importantly, the KRMK (Lysine-Arginine-Methionine-Lysine) motif in the carboxyl-terminus of GluA1 is suggested to be an AP2 binding site, but the exact function has not been defined. Moreover, the GluA1 KRMK motif is closely located to one of GluA1 phosphorylation sites, serine 845 (S845), and GluA1 S845 dephosphorylation is suggested to enhance endocytosis during long-term depression. In fact, we show that an increase in GluA1 S845 phosphorylation by two distinct forms of synaptic plasticity, long-term potentiation and synaptic up-scaling, diminishes the binding of the AP2 adaptor. This reduces endocytosis, resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated endocytosis of AMPARs.

neuroscience↗