17394
mGluR5 Expression Is Required for NMDA-Receptor Dependent Forms of Plasticity in Mouse Visual Cortex
Saturday, May 17, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
M. Sidorov1, E. Kaplan1, S. Tagliatela1 and M. F. Bear2, (1)Massachusetts Institute of Technology, Cambridge, MA, (2)The Picower Institute for Learning and Memory, Cambridge, MA
Background: Fragile X (FX) is a single-gene disorder associated with autism. Fragile X is caused by a mutation in the
Fmr1 gene, leading to a lack of production of its protein product, Fragile X mental retardation protein (FMRP). FMRP normally acts as an inhibitor of protein synthesis at the synapse, and the lack of FMRP leads to increased protein synthesis. Fragile X is essentially thought of as a disease of excess – excessive protein synthesis causes numerous symptoms, and interventions designed to reduce protein synthesis back to normal levels are being considered as possible therapies. Metabotropic glutamate receptors (mGluR) signaling is coupled to synaptic protein synthesis. Therefore inhibiting this pathway could potentially rescue the enhanced protein synthesis seen in Fragile X. The “mGluR theory of Fragile X” has been extensively tested. Most recently, chronic administration of the novel mGluR5 antagonist CTEP corrected numerous FX mouse phenotypes.
Objectives: We sought to understand how mGluR5 regulates experience-dependent synaptic plasticity in mouse visual cortex. This is critically important because mGluR5 antagonists are currently in clinical trials for FX.
Methods: We measured synaptic plasticity in vitro using both whole-cell and field potential recordings, and in vivo in an awake, head-fixed setup where the animal views visual stimuli.
Results: Surprisingly, we found that mGluR5 is required for long-term depression (LTD) in slice and forms of experience-dependent plasticity in vivo. Additionally, chronic administration of the mGluR5 antagonist CTEP results in similar phenotypes seen in the mGluR5 knockout mouse.
Conclusions: This work suggests that signaling through mGluR5 during development is crucial to establish forms of NMDA receptor-dependent plasticity in adulthood. In the context of Fragile X, this work suggests that the timing and location of mGluR5-mediated pharmacological therapies are crucial.
