A Cellular Mechanism of Learning-Induced Enhancement of Synaptic Inhibition: PKC-Dependent Upregulation of KCC2 Activation

Adi Kfir,Richa Awasthi,Sourav Ghosh,Raphael Lamprecht,Sankhanava Kundu,Edi Barkai,Blesson Paul

doi:10.1038/s41598-020-57626-2

Adi Kfir, Richa Awasthi + Show 5 more

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https://doi.org/10.1038/s41598-020-57626-2

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Journal: Scientific Reports	Publication Date: Jan 22, 2020
Citations: 6	License type: open-access

Affiliation: University of Haifa

Abstract

Long-term memory of complex olfactory learning is expressed by wide spread enhancement in excitatory and inhibitory synaptic transmission onto piriform cortex pyramidal neurons. A particularly interesting modification in synaptic inhibition is the hyperpolarization of the reversal potential of the fast post synaptic inhibitory potential (fIPSP). Here we study the mechanism underlying the maintenance of such a shift in the fIPSP. Blocking of the neuronal specific K+-Cl− co-transporter (KCC2) in neurons of trained rats significantly depolarized the averaged fIPSP reversal potential of the spontaneous miniature inhibitory post synaptic currents (mIPSCs), to the averaged pre-training level. A similar effect was obtained by blocking PKC, which was previously shown to upregulate KCC2. Accordingly, the level of PKC-dependent phosphorylation of KCC2, at the serine 940 site, was significantly increased after learning. In contrast, blocking two other key second messenger systems CaMKII and PKA, which have no phosphorylation sites on KCC2, had no effect on the fIPSP reversal potential. Importantly, the PKC inhibitor also reduced the averaged amplitude of the spontaneous miniature excitatory synaptic currents (mEPSCs) in neurons of trained rats only, to the pre-training level. We conclude that learning-induced hyper-polarization of the fIPSP reversal potential is mediated by PKC-dependent increase of KCC2 phosphorylation.

Highlights

The mechanisms underlying learning-induced and activity-induced plasticity of synaptic inhibition have been the subject of an increasing number of studies[9,15,16,17]
We show that learning-induced hyperpolarization of the reversal potential of the fast GABAA-mediated fast synaptic inhibition is maintained by enhanced KCC2 activation and requires persistent activation of PKC for its long-term maintenance
Neurons from pseudo trained and naïve rats had an identical averaged reversal potential for the early IPSP, and values obtained in neurons from these two groups were combined to a single control group

Summary

Introduction

The mechanisms underlying learning-induced and activity-induced plasticity of synaptic inhibition have been the subject of an increasing number of studies[9,15,16,17]. We previously showed that complex olfactory-discrimination (OD) learning results in a long-lasting enhancement of GABAA-mediated inhibitory synaptic transmission in piriform cortex pyramidal neurons, which is widely spread throughout the piriform cortex pyramidal cell population[9,11,13,14,16,18]. Such learning-induced enhanced inhibition is mediated by two mechanisms; increased single-channel conductance of the GABAA-channel receptor[11,13] and a hyperpolarizing shift in the chloride current mediated fIPSP reversal potential,[9,18]. Enhanced KCC2 activity, which should result in increase of this synaptic current, can be induced by phosphorylation of the serine 940 residue on the cytoplasmic C-terminal domain[23,24,25]

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