Effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices

doi:10.1016/j.pnpbp.2006.09.008

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 31, Issue 2, 30 March 2007, Pages 343-347

https://doi.org/10.1016/j.pnpbp.2006.09.008 Get rights and content

Abstract

Although it has long been suggested that lithium has robust neuroplastic actions, and these actions lead to an enhancement on synaptic plasticity, the effects of lithium treatment on synaptic plasticity have been rarely studied. This study examined the effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus (DG) of hippocampal slices in the rats. Young adult rats were intraperitoneally administered a daily dose of 1 mgEq LiCl or saline-vehicle for 14 days. Twelve hours after the last injections, the input/output (I/0) responses of field excitatory postsynaptic potentials (fEPSP) and the long-term potentiation (LTP) of fEPSP and population spikes (PS) were determined in the DG of hippocampal slices prepared from the animals treated with lithium or vehicle. Treatment of lithium for 14 days significantly increased the I/O responses of fEPSP and the LTP of fEPSP and PS. These results indicate that sub-chronic treatment of lithium increases the excitatory postsynaptic responses, synaptic strength and the cell firing of the granule cells in the DG of the hippocampus.

Introduction

The neuroplastic theory of bipolar disorder proposes that detrimental neuroplastic changes may impair normal synaptic transmissions in neuronal circuits involved in the pathophysiology of bipolar disorder (Manji et al., 2001). Lithium may augment synaptic plasticity by blocking neuronal death, enhancing neurogenesis, stimulating the proliferation of dendrites and facilitating synaptic transmission (Manji et al., 1999). These cellular actions of lithium have been shown to be associated with up-regulation of diverse neurotrophic and neuroprotective factors such as brain-derived neurotrophic factor (BDNF), B-cell CLL/lymphoma 2 (Bcl-2) and glia-derived neurotrophic factor (GDNF) and transcription factors involved in the gene expression of these and other neurotrophic factors including cyclic adenosine monophosphate response element-binding protein (CREB) (Fukumoto et al., 2001, Manji et al., 2001, Angelucci et al., 2003). These molecules are known to play essential roles in maintaining normal synaptic transmission and plasticity (Silva et al., 1998, McAllister et al., 1999, Fields and Stevens-Graham, 2002). Brain imaging studies have shown that the chronic administration of lithium increased the volume of the gray matter in patients with bipolar disorder (Moore et al., 2000a, Sassi et al., 2002), and this increase might be associated with the proliferation of dendrites, suggesting that lithium may enhance synaptic connections (Moore et al., 2000b). Based on these molecular, cellular and brain imaging studies, it has been postulated that the major converging consequence of these diverse neuroplastic actions of lithium may lead to the enhancement of synaptic plasticity and thereby reverse impaired synaptic communications in neuronal circuits involved in the pathophysiology of mood disorders and produce therapeutic efficacy (Manji et al., 2001). This neuroplastic theory has been developed primarily based on data from molecular and cellular studies with cultured cells or animals. Although this theory has been widely accepted, the effects of lithium on synaptic plasticity have been rarely studied. This theory can be directly tested by investigating the effects of lithium treatment on synaptic plasticity, using electrophysiological techniques. In this study, we examined the effects of daily intraperitoneal (IP) administration of lithium for 14 days on the electrophysiological parameters of synaptic plasticity including the input/output (I/O) responses of field excitatory postsynaptic potentials (fEPSP) and the long-term potentiation (LTP) of fEPSP and population spikes (PS) in the dentate gyrus (DG) of hippocampal slices prepared from young adult rats administered with lithium.

Section snippets

Animals

Forty five-day old male Sprague-Dawley rats weighing 150 to 200 g at procurement were housed in pairs and fed with chow, and water was freely available ad libitum with a light/dark cycle of 12/12 h for 1 week of acclimatization before experiments began. LiCl (1 mEq/kg/day) or saline (vehicle) was injected IP into the animals twice a day. Twelve hours after the last administration of LiCl or vehicle, animals were sacrificed during the light period of the cycle. The animals were cared and treated

Results

To examine the effects of sub-chronic treatment of lithium on synaptic plasticity, young adult rats were administered IP with a low dose (1 mEq/kg/day) of LiCl or saline for 14 days. To mimic a conventional way to administer lithium to patients and stabilize lithium levels during the administration of the drug, lithium was administered twice per day. The animals were sacrificed, and the blood levels of lithium were determined in 12 h after the last administration of lithium, which is the time

Discussion

In the present study, we report that lithium administration for 14 days increases the I/O responses of fEPSP (Fig. 1) and LTP of fEPSP (Fig. 2 and PS (Fig. 3) in the DG of the adult rat hippocampus. Fourteen days of lithium treatment is long enough to produce neuroplastic actions through the gene expression of proteins involved in neuronal plasticity and synaptic plasticity and produces clinical efficacy (Hirschfeld et al., 2000, Lenox and Frazer, 2002). Son et al. (2003) reported that the

Conclusion

This study reports that sub-chronic lithium treatment enhances synaptic plasticity and cell firing of the granule cells in the DG of the rat hippocampus. These electrophysiological findings confirm the neuroplastic theory that lithium may increase synaptic plasticity, which has been developed primarily based on molecular biological studies. Although many possible molecular mechanisms may be suggested to be associated with the lithium-induced enhancement of synaptic plasticity, it remains to be

Acknowledgments

This study was supported by the Cleveland Veterans Affair Medical Center Research and Education Foundation Fund. We thank Rebecca Russell, Ph.D. in the Department of Psychiatry, the Case Western Reserve University for technical assistance. We also thank Dr. Bryan Roth in the Departments of Psychiatry and Neurochemistry at the Case Western Reserve University for providing valuable feedback on the discussion and editing of the manuscript. The authors have no conflict of interest.

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Citation Excerpt :
Although multiple lines of evidence support this theory, few studies have examined the effects of lithium on synaptic plasticity. We and other groups have reported that lithium treatment up-regulates synaptic plasticity in the dentate gyrus (DG) [31,35]. However, to the best of our knowledge, no studies have examined the effects of lithium treatment on synaptic plasticity in the hippocampus proper, a major locus of the neuropathology of bipolar disorder [36].
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In the present study, to examine the effects of lithium and olanzapine on synaptic plasticity, we examined the effects of chronic treatment with lithium and olanzapine on long-term potentiation (LTP) and input and output (I/O) responses of field excitatory postsynaptic potentials (fEPSP) of CA1 pyramidal cells in hippocampal slices prepared from rats administered the drugs for 4 weeks. Our results show that 4 weeks of lithium treatment magnified LTP of CA1 pyramidal cells. However, the same treatment with olanzapine did not magnify LTP of CA1 pyramidal cells. Four weeks of treatment with lithium did not alter I/O responses of CA1 pyramidal cells. However, the same treatment with olanzapine increased I/O responses of CA1 pyramidal cells. The results suggest that lithium up-regulates synaptic plasticity in the hippocampus, and olanzapine increases synaptic transmission without apparent changes in LTP in the hippocampus.

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Effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices

Abstract

Introduction

Section snippets

Animals

Results

Discussion

Conclusion

Acknowledgments

Trends Neurosci

Trends Neurosci

Neuropharmacology

Neuropharmacology

Biol Psychiatry

Lancet

Biol Psychiatry

Neurosci Lett

Biochem Biophys Res Commun

Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression

Int J Neuropsychopharmacol

Drugs and treatment of psychotic disorders: psychosis and mania

Neurophysiological changes in the in vitro rat hippocampus following chronic lithium administration

Brain Res

Reductions in cholesterol and synaptic markers in association cortex in mood disorders

Bipolar Disord

New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment

Eur J Neurosci

Enhancement of hippocampal neurogenesis by lithium

J Neurochem

Dietary lithium induces regional increases of mRNA encoding cysteine string protein in rat brain

J Neurosci Res

Convergent effects of lithium and valproate on the expression of proteins associated with large dense core vesicles in NGF-differentiated PC12 cells

Neuropsychopharmacology

Leitmotifs in the biochemistry of LTP induction: amplification, integration and coordination

J Neurochem