MiR-134-dependent regulation of Pumilio-2 is necessary for homeostatic synaptic depression

Authors


Abstract

Neurons employ a set of homeostatic plasticity mechanisms to counterbalance altered levels of network activity. The molecular mechanisms underlying homeostatic plasticity in response to increased network excitability are still poorly understood. Here, we describe a sequential homeostatic synaptic depression mechanism in primary hippocampal neurons involving miRNA-dependent translational regulation. This mechanism consists of an initial phase of synapse elimination followed by a reinforcing phase of synaptic downscaling. The activity-regulated microRNA miR-134 is necessary for both synapse elimination and the structural rearrangements leading to synaptic downscaling. Results from miR-134 inhibition further uncover a differential requirement for GluA1/2 subunits for the functional expression of homeostatic synaptic depression. Downregulation of the miR-134 target Pumilio-2 in response to chronic activity, which selectively occurs in the synapto-dendritic compartment, is required for miR-134-mediated homeostatic synaptic depression. We further identified polo-like kinase 2 (Plk2) as a novel target of Pumilio-2 involved in the control of GluA2 surface expression. In summary, we have described a novel pathway of homeostatic plasticity that stabilizes neuronal circuits in response to increased network activity.

Synopsis

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The neuronal activity regulated miR-134/Pum2/Plk2 pathway mediates synaptic depression in primary hippocampal neurons by inhibiting the AMPA-type glutamate receptor GluA2.

  • Homeostatic synaptic depression (HSD) occurs in two phases: synapse elimination followed by synaptic downscaling.
  • miR-134 is required for synapse elimination and for structural, but not functional, synaptic downscaling.
  • miR-134-dependent repression of Pumilio-2 is involved in HSD.
  • miR-134/Pumilio-2 regulate surface expression of the AMPA-type glutamate receptor GluA2 during HSD.
  • The Plk2/SPAR pathway is an important downstream effector of miR-134/Pumilio-2 during HSD.