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Early postnatal exposure to lithium in vitro induces changes in AMPAR mEPSCs and vesicular recycling at hippocampal glutamatergic synapses

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Abstract

Lithium is an effective mood stabilizer but its use is associated with many side effects. Electrophysiological recordings of miniature excitatory postsynaptic currents (mEPSCs) mediated by glutamate receptor AMPA-subtype (AMPARs) in hippocampal pyramidal neurons revealed that CLi (therapeutic concentration of 1 mM lithium, from days in vitro 4–10) decreased the mean amplitude and mean rectification index (RI) of AMPAR mEPSCs. Lowered mean RI indicate that contribution of Ca2+-permeable AMPARs in synaptic events is higher in CLi neurons (supported by experiments sensitive to Ca2+-permeable AMPAR modulation). Co-inhibiting PKA, GSK-3β and glutamate reuptake was necessary to bring about changes in AMPAR mEPSCs similar to that seen in CLi neurons. FM1-43 experiments revealed that recycling pool size was affected in CLi cultures. Results from minimum loading, chlorpromazine treatment and hyperosmotic treatment experiments indicate that endocytosis in CLi is affected while not much difference is seen in modes of exocytosis. CLi cultures did not show the high KCl associated presynaptic potentiation observed in control cultures. This study, by calling attention to long-term lithium-exposure-induced synaptic changes, might have implications in understanding the side effects such as CNS complications occurring in perinatally exposed babies and cognitive dulling seen in patients on lithium treatment.

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Abbreviations

AMPARs:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors

CLi:

long-term lithium-treated cultures

DFMO:

Di-fluoro-methyl-ornithine

GSK-3β:

glycogen synthase kinase-3β

I-V curve:

current–voltage curve

mEPSCs:

miniature excitatory postsynaptic currents

NASPM:

N-acetyl spermine

NMDARs:

N-methyl-d-aspartate receptors

P in P0:

P2 and P8, postnatal day

PKA:

protein kinase A

PKC:

protein kinase C

RI:

rectification index

RP:

reserve pool

RRP:

readily releasable pool

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Acknowledgements

We would like to acknowledge Council of Scientific and Industrial Research (CSIR), India, for extending financial support in the form of CSIR fellowship to SMA.

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Correspondence to Sujit K Sikdar.

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Corresponding editor: Neeraj Jain

[Ankolekar SM and Sikdar SK 2015 Early postnatal exposure to lithium in vitro induces changes in AMPAR mEPSCs and vesicular recycling at hippocampal glutamatergic synapses. J. Biosci. 40 1–16] DOI 10.1007/s12038-015-9527-3

Supplementary materials pertaining to this article are available on the Journal of Biosciences Website at http://www.ias.ac.in/jbiosci/jun2015/supp/Ankolekar.pdf

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Ankolekar, S.M., Sikdar, S.K. Early postnatal exposure to lithium in vitro induces changes in AMPAR mEPSCs and vesicular recycling at hippocampal glutamatergic synapses. J Biosci 40, 339–354 (2015). https://doi.org/10.1007/s12038-015-9527-3

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