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Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons

Abstract

Neural activity regulates the number and properties of GABAergic synapses in the brain, but the mechanisms underlying these changes are unclear. We found that blocking spike activity globally in developing hippocampal neurons from rats reduced the density of GABAergic terminals as well as the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Chronic inactivity later in development led to a reduction in the mIPSC amplitude, without any change in GABAergic synapse density. By contrast, hyperpolarizing or abolishing spike activity in single neurons did not alter GABAergic synaptic inputs. Suppressing activity in individual presynaptic GABAergic neurons also failed to decrease synaptic output. Our results indicate that GABAergic synapses are regulated by the level of activity in surrounding neurons. Notably, we found that the expression of GABAergic plasticity involves changes in the amount of neurotransmitter in individual vesicles.

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Figure 1: Chronic suppression of activity causes a reduction in number of inhibitory synapses.
Figure 2: The frequency and amplitude of mIPSCs are reduced by inactivity.
Figure 3: Suppression of activity in established cultures reduces functional inhibition.
Figure 4: Chronic hyperpolarization of an individual postsynaptic neuron does not reduce the inhibition it receives.
Figure 5: The frequency and amplitude of mIPSCs are unaltered by chronic hyperpolarization of individual postsynaptic neurons.
Figure 6: Elimination of sodium action potentials in single neurons does not affect incoming GABAergic synapses.
Figure 7: Chronic suppression of activity in individual presynaptic GABAergic neurons does not reduce synaptic output.
Figure 8: Presynaptic contribution to reduction in mIPSC amplitude.

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Acknowledgements

We thank M. Kinet for help with some of the experiments, and members of our lab for critical discussions. We are grateful to P. Shrager (University of Rochester, Rochester, New York) for the gift of the shRNA plasmids. This work was supported by grants from the US National Institutes of Health, the National Science Foundation, the EJLB Foundation and the Klingenstein Fund.

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Correspondence to Venkatesh N Murthy.

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Supplementary information

Supplementary Fig. 1

Reduction in GABAergic synapses triggered by chronic suppression also occurs on inhibitory targets. (PDF 2469 kb)

Supplementary Fig. 2

BDNF treatment counters the effects of chronic inactivity. (PDF 1170 kb)

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Hartman, K., Pal, S., Burrone, J. et al. Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons. Nat Neurosci 9, 642–649 (2006). https://doi.org/10.1038/nn1677

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