Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons

• Published in: Bipolar disorders 2015-05, Vol.17 (3), p.278-290
• Main Authors: Park, Sung Woo, Lee, Jung Goo, Seo, Mi Kyoung, Cho, Hye Yeon, Lee, Chan Hong, Lee, Ji Heon, Lee, Bong Ju, Baek, Jun Hyung, Seol, Wongi, Kim, Young Hoon
• Format: Article
• Language: English
• Subjects: Animals; Antimanic Agents - pharmacology; Bipolar Disorder; Brain-Derived Neurotrophic Factor - drug effects; Brain-Derived Neurotrophic Factor - metabolism; Cell Adhesion Molecules, Neuronal - drug effects; Cell Adhesion Molecules, Neuronal - metabolism; Dendrites - drug effects; dendritic outgrowth; Disks Large Homolog 4 Protein; Hippocampus - cytology; Intracellular Signaling Peptides and Proteins - drug effects; Intracellular Signaling Peptides and Proteins - metabolism; Lithium Compounds - pharmacology; Membrane Proteins - drug effects; Membrane Proteins - metabolism; mood-stabilizing drugs; neural plasticity; Neurons - drug effects; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Rats; signaling; synaptic proteins; Synaptophysin - drug effects; Synaptophysin - metabolism; Triazines - pharmacology; Valproic Acid - pharmacology
• ISSN: 1398-5647; 1399-5618
• DOI: 10.1111/bdi.12262

Objectives Mood‐stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood‐stabilizing drugs produce similar effects in primary hippocampal neurons. Methods The effects of the mood‐stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins – that is, brain‐derived neurotrophic factor (BDNF), postsynaptic density protein‐95 (PSD‐95), neuroligin 1 (NLG1), β‐neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27‐deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium. Results Li (0.5–2.0 mM), VPA (0.5–2.0 mM), CBZ (0.01–0.10 mM), and LTG (0.01–0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3‐kinase, extracellular signal‐regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation‐induced decreases in BDNF, PSD‐95, NLG1, β‐neurexin, and SYP levels, whereas LTG did not. Conclusions These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood‐stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures.