Elsevier

Neuroscience

Volume 161, Issue 4, 21 July 2009, Pages 1126-1134
Neuroscience

Neuropharmacology
Research Paper
Glutamate-mediated calcium signaling: A potential target for lithium action

https://doi.org/10.1016/j.neuroscience.2009.04.013Get rights and content

Abstract

Bipolar disorder and schizophrenia are two debilitating mental health disorders associated with both severe impairment and increased suicide risk. Several lines of evidence indicate that these disorders are associated with disturbances in the glutamate system. For almost half a century, lithium has been the most effective drug for treatment of mood disorders. Lithium is still used mainly on empiric grounds and its molecular mechanisms of action are still largely unknown. This study was designed to explore the effects of continuous lithium exposure, in therapeutically relevant concentration, on the glutamate-mediated Ca2+ response in rat primary hippocampal neurons. We show that lithium treatment is associated with multiple perturbations in calcium signaling. Lithium attenuated calcium release after activation of both metabotropic glutamate receptors (mGluR)1/5 as well as muscarinic cholinergic receptors, two different Gq-coupled receptors. The attenuation of the calcium response was, for mGluR5 receptors, found to be associated with a downregulation of the plasma membrane expression of this receptor. Lithium also attenuated calcium influx after activation of the N-methyl-D-aspartate receptor, without affecting its cell surface expression. Furthermore lithium treatment was associated with a decrease in intracellular calcium concentration and a reduction of calcium content in intracellular stores. Thus we have shown that lithium attenuates the effects of glutamate-mediated calcium signaling and regulates intracellular calcium levels as well as calcium turnover in hippocampal neurons. These effects can be expected to influence the communication within and between neurons in a variety of ways since calcium may be considered as the most common and the most versatile signaling molecule in neurons.

Section snippets

Preparation of primary culture of hippocampal neurons

Primary cultures of hippocampal neurons were prepared from 18-day-old Sprague–Dawley rat embryos, as described (Mao and Wang, 2003) with few modifications. All experiments were approved by the local committee on Ethics for Animal Experimentation, Stockholm, Sweden, in accordance to the Swedish national law on the ethical use of animal. All efforts were made to minimize the number of animals used and their suffering. Briefly, hippocampi were dissected and placed into cold Hanks' balance salt

Seven days of lithium treatment reduces glutamate-mediated Ca2+ response in hippocampal neurons

The effect of glutamate on [Ca2+]i was studied in primary cultures of rat hippocampal neurons. Neurons were identified according to their characteristic morphological features under the microscope and by their capacity to respond to NMDA. The majority of neurons had a pyramidal soma with two or more primary dendrites. The neurons accounted for the majority of cells on the coverslip under the above-described culturing conditions. When cells were exposed to glutamate (1 μM), an almost immediate

Discussion

It has been postulated for many years that perturbation in calcium signaling is one mechanism by which lithium can exert its action in mood disorders and other neuropsychiatric diseases (Wasserman et al 2004, Perova et al 2007, Bauer et al 2003). Nevertheless, there are relatively few studies that have examined the effect of lithium on calcium signaling pathways in neurons. Here we show that seven days' exposure of neurons to lithium is associated with multiple perturbations in calcium

Acknowledgments

This work was supported by grants from the Swedish Research Council, the Märtha and Gunnar V. Philipson Foundation and the Persson Family Foundation.

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