Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling

Steffen Fricke,Kristin Metzdorf,Marta Zagrebelsky,Stefan Haak,Melanie Ohm,Martin Korte,Martin Heine

doi:10.1016/j.celrep.2019.09.015

Steffen Fricke, Kristin Metzdorf + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2019.09.015

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Abstract

Precisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABAAR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABAAR diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABAARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.

Highlights

As inhibitory synaptic transmission plays a crucial role in shaping the function of the neuronal network, adjustments in its strength represent a key regulatory mechanism for different brain processes, such as learning and memory (Barron et al, 2017; Isaacson and Scanziani, 2011; Maffei, 2011)
We report that blocking Nogo-A signaling via the S1PR2 in pyramidal hippocampal neurons results in the rapid increase in GABAAR lateral motility associated with a decrease in their number at synapses, leading to a decrease in the amplitude of GABAergic miniature inhibitory postsynaptic currents
We found that the increase in GABAAR motility upon Nogo-A loss of function is correlated with an increase in Ca2+ transient amplitude and CaN-mediated dephosphorylation of the GABAAR g2 subunit at serine 327 (Ser327)

Summary

Introduction

As inhibitory synaptic transmission plays a crucial role in shaping the function of the neuronal network, adjustments in its strength represent a key regulatory mechanism for different brain processes, such as learning and memory (Barron et al, 2017; Isaacson and Scanziani, 2011; Maffei, 2011). While extracellular signaling increasing GABAAR diffusion and suppressing inhibitory transmission have been identified (e.g., brainderived neurotrophic factor [BDNF] signaling and increased neuronal activity [Bru€nig et al, 2001; Goodkin et al, 2005]), little is known about molecules limiting their diffusion and thereby strengthening inhibition. Addressing this question is crucial for understanding how the appropriate excitation and inhibition balance in the brain is maintained, allowing the tight regulation of plastic processes

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