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.
Similar content being viewed by others
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
References
Akaneya Y, Sohya K, Kitamura A, Kimura F, Washburn C, Zhou R, Ninan I, Tsumoto T, et al. 2010 Ephrin-A5 and EphA5 interaction induces synaptogenesis during early hippocampal development. PLoS One 5 1–20
Bonanomi D, Menegon A, Miccio A, Ferrari G, Corradi A, Kao H-T, Benfenati F and Valtorta F 2005 Phosphorylation of synapsin I by cAMP-dependent protein kinase controls synaptic vesicle dynamics in developing neurons. J. Neurosci. 25 7299–7308
Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N and Manji HK 2000 Enhancement of hippocampal neurogenesis by lithium. J. Neurochem. 75 1729–1734
Clayton EL and Cousin MA 2009 The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles. J. Neurochem. 111 901–914
Clayton EL, Evans GJO and Cousin MA 2008 Bulk synaptic vesicle endocytosis is rapidly triggered during strong stimulation. J. Neurosci. 28 6627–6632
Clayton EL, Sue N, Smillie KJ, O’Leary T, Bache N, Cheung G, Cole AR, Wyllie DJ, et al. 2010 Dynamin I phosphorylation by GSK3 controls, activity-dependent bulk endocytosis of synaptic vesicles. Nat. Neurosci. 13 845–853
Cohen-Cory S 2002 The developing synapse: construction and modulation of synaptic structures and circuits. Science. 298 770–776
Cottrell JR, Dube GR, Egles C and Liu G 2000 Distribution, density, and clustering of functional glutamate receptors before and after synaptogenesis in hippocampal neurons. J. Neurophysiol. 84 1573–1587
Du J, Creson TK, Wu L-J, Ren M, Gray NA, Falke C, Wei Y, Wang Y, et al. 2008 The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. J. Neurosci. 28 68–79
Dunner DL 2000 Optimising lithium treatment. J. Clin. Pscychiatry. 61 76–81
Ehlers MD 2000 Reinsertion or Degradation of AMPA Receptors determined by activity-dependent endocytic sorting. Neuron. 28 511–525
Ferguson SM, Brasnjo G, Hayashi M, Wölfel M, Collesi C, Giovedi S, Raimondi A, Gong L-W, et al. 2007 Selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science 316 570–574
Gilad GM, Gilad VH and Casero RA Jr 1994 Lithium exerts a time-dependent and tissue-selective attenuation of the dexamethasone-induced polyamine response in rat brain and liver. Brain Res. 636 187–192
Gilad GM and Gilad VH 2007 Astroglia growth retardation and increased microglia proliferation by lithium and ornithine decarboxylase inhibitor in rat cerebellar cultures: Cytotoxicity by combined lithium and polyamine inhibition. J. Neurosci. Res. 85 594–601
Hashimoto R, Hough C, Nakazawa T, Yamamoto T and Chuang D-M 2002 Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J. Neurochem. 80 589–597
Iqbal Z 1995 Excitatory amino acid receptor-mediated neuronal signal transduction: modulation by polyamines and calcium. Mol. Cell. Biochem. 149 233–240
Kent A 2008 Psychiatric disorders in pregnancy. Obstet. Gynaecol. Reprod. Med. 19 37–41
Koike M, Iino M and Ozawa S 1997 Blocking effect of 1-naphthyl acetyl spermine on Ca2+-permeable AMPA receptors in cultured rat hippocampal neurons. Neurosci. Res. 29 27–36
Kugaya A and Sanacora G 2005 Beyond monoamines: Glutamatergic function in mood disorders. CNS Spectr. 10 808–819
Lee AL, Ogle WO and Sapolsky RM 2002 Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. 4 117–128
Leenders AGM and Sheng Z-H 2005 Modulation of neurotransmitter release by the second messenger-activated protein kinases: Implications for presynaptic plasticity. Pharmacol. Therapeut. 105 69–84
Lenox RH and Wang L 2003 Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol. Psychiat. 8 135–144
Loepke AW, McGowan FX Jr and Soriano SG 2008 CON: The toxic effects of anesthetics in the developing brain: The clinical perspective. Int. Anesth. Res. Soc. 106 1664–1669
Lu H-C, She W-C, Plas DT, Neumann PE, Janz R and Crair MC 2003 Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical ‘barrel’ map development. Nat. Neurosci. 6 939–942
Manji HK, Drevets WC and Charney DS 2001 The cellular neurobiology of depression. Nat. Med. 7 541–547
Mori S, Zanardi R, Popoli M, Smeraldi E, Racagni G and Parez J 1996 Inhibitory effect of lithium ion on cAMP dependent phosphorylation system. Life Sci. 59 PL 99–104
Morrell P, Sutherland GR, Buamah Moo PK and Bain HH 1983 Lithium toxicity in a neonate. Arch. Dis. Child. 58 539–541
Mozhayeva MG, Sara Y, Liu X and Kavalali ET 2002 The Development of Vesicle Pools during Maturation of Hippocampal Synapses. J. Neurosci. 22 654–665
Newport DJ, Viguera AC, Beach AJ, Ritchie JC, Cohen LS and Stowe ZN 2005 Lithium placental passage and obstetrical outcome: Implications for clinical management during late pregnancy. Am. J. Psychiatry. 162 2162–2170
Noh K-M, Yokota H, Mashiko T, Castillo PE, Zukin RS and Bennett VLM 2005 Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Proc. Natl. Acad. Sci. USA 102 12230–12235
Nonaka S, Hough CJ and Chuang D-M 1998 Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proc. Natl. Acad. Sci. USA 95 2642–2647
Pellegrini-Giampietro DE, Gorter JA, Bennett MVL and Zukin RS 1997 The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders. Trends Neurosci. 20 464–470
Phiel CJ and Klein PS 2001 Molecular targets of lithium action. Ann. Rev. Pharmacol. Toxicol. 41 789–813
Rao SP and Sikdar SK 2004 Estradiol-induced changes in the activity of hippocampal neurons in network culture are suppressed by co-incubation with gabapentin. Brain Res. 1022 126–136
Richards DA, Guatimosim C and Betz WJ 2000 Two endocytic recycling routes selectively fill two vesicle pools in frog motor nerve terminals. Neuron. 27 551–559
Roisin M-P, Leinekugel X and Tremblay E 1997 Implication of protein kinase C in mechanisms of potassium- induced long-term potentiation in rat hippocampal slices. Brain Res. 745 222–230
Sara Y, Mozhayeva MG, Liu X and Kavalali ET 2002 Fast Vesicle Recycling Supports Neurotransmission during Sustained Stimulation at Hippocampal Synapses. J. Neurosci. 22 1608–1617
Shin J, Shen F and Huguenard JR 2005 Polyamines modulate AMPA receptor-dependent synaptic responses in immature layer V pyramidal neurons. J. Neurophysiol. 93 2634–2643
Sjöholm A, Welsh N and Hellerström C 1992 Lithium increases DNA replication, polyamine content, and insulin secretion by rat pancreatic beta-cells. Am. J. Physiol. 262 C391–5
Sparapani M, Virgili M, Ortali F and Contestabile A 1997 Effects of chronic lithium treatment on ornithine decarboxylase induction and excitotoxic neuropathology in the rat. Brain Res. 765 164–168
Speese SD and Budnik V 2007 Wnts: Up-and-coming at the synapse. Trends Neurosci. 30 268–275
Srinivas KV, Jain R, Saurav S and Sikdar SK 2007 Small-world network topology of hippocampal neuronal network is lost, in an in vitro glutamate injury model of epilepsy. Eur. J. Neurosci. 25 3276–3286
Van Den Bosch L, Vandenberghe W, Klaassen H, Van Houtte E and Robberecht W 2000 Ca2+-permeable AMPA receptors and selective vulnerability of motor neurons. J. Neurol. Sci. 180 29–34
van den Pol AN, Obrietan K, Belousov AB, Yang Y and Heller HC 1998 Early Synaptogenesis In Vitro: Role of Axon Target Distance. J. Comp. Neurol. 399 541–560
Volmer R, Monnet C and Gonzalez-Dunia D 2006 Borna Disease Virus Blocks Potentiation of Presynaptic Activity through Inhibition of Protein Kinase C Signaling. PLoS Pathog. 2 e19
Wang H-Y, Johnson GP and Friedman E 2001 Lithium treatment inhibits protein kinase C translocation in rat brain cortex. Psychopharmacology. 158 80–86
Weiss JH and Sensi SL 2000 Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration. Trends Neurosci. 23 365–371
Wierenga CJ, Ibata K and Turrigiano GG 2005 Postsynaptic expression of homeostatic plasticity at neocortical synapses. J. Neurosci. 25 2895–2905
Zarate CA Jr and Manji HK 2008 The Role of AMPA Receptor modulation in the treatment of neuropsychiatric diseases. Exp. Neurol. 211 7–10
Zhu JJ, Esteban JA, Hayashi Y and Malinow R 2000 Synaptic potentiation during early development: delivery of GluR4-containing AMPA receptors by spontaneous activity. Nat. Neurosci. 3 1098–1106
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
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
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(PDF 2.61 MB)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12038-015-9527-3