Title:Chronic Lithium Treatment Alters NMDA and AMPA Receptor Synaptic
Availability and Dendritic Spine Organization in the Rat Hippocampus
Volume: 22
Issue: 12
Author(s): Lucia Caffino, Giorgia Targa, Anne Stephanie Mallien, Francesca Mottarlini, Beatrice Rizzi, Judith R. Homberg, Peter Gass and Fabio Fumagalli*
Affiliation:
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
Keywords:
Bipolar disorder, lithium, glutamate, NMDA receptor, AMPA receptor, hippocampus, BDNF.
Abstract:
Background: The mechanisms underlying the action of lithium (LiCl) in bipolar disorder
(BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized
by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down
glutamatergic signaling abnormalities.
Objective: In this study, taking advantage of western blot and confocal microscopy, we used a combination
of integrative molecular and morphological approaches in rats exposed to repeated administration
of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time
points, i.e., 24 hours and 7 days after the last exposure.
Results: We report that repeated LiCl treatment activates multiple, parallel, but also converging forms
of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a
wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing
NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative
of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic
spine morphology, such as increased length and head diameter of such spines. These changes may
counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors
as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors.
Conclusion: Our findings highlight a previously unknown cohesive picture of the glutamatergic implications
of LiCl action that persist long after the end of its administration, revealing for the first time
a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition
and structure.
