Lithium and brain plasticity - studies on glial cell changes and electroconvulsive treatment-induced amnesia in rats

Depression and bipolar disorder, collectively known as mood disorders, are devastating, common and often chronic illnesses. Imaging studies of patients with mood disorders have demonstrated structural changes in several brain regions implicated in mood regulation. Furthermore, bipolar disorder is associated with white matter abnormalities and post mortem analysis of brain tissue from patients with mood disorders have shown glial cell pathology. Electroconvulsive therapy (ECT) and pharmacological treatment with lithium have been used in the treatment of mood disorders for over 70 respectively 60 years, but the mechanisms behind their therapeutic effects remain elusive. We have previously shown increased neurogenesis and NG2 cell proliferation in a rat model of ECT, electroconvulsive seizures (ECS). NG2 cells can differentiate into mature myelinating oligodendrocytes in the adult brain. Moreover, given the fact they are an abundant proliferative cell type in all areas implicated in mood disorders and with a unique capacity to respond directly to neuronal signalling changes through their specialized contacts with neurons, NG2 cells are highly interesting in the context of mood disorder-associated white and grey matter changes. In paper I we show that chronic lithium treatment unlike its stimulating effect on hippocampal neurogenesis, decreased NG2 cell proliferation in the rat dentate hilus of hippocampus, amygdala and corpus callosum. Decreased proliferation could reflect decreased oligodendrogenesis or possibly cell cycle arrest in favour of differentiation into oligodendrocytes. Thus, in paper II we investigated the effect of lithium on remyelination and oligodendrogenesis in corpus callosum after chemically induced demyelination. We found that lithium treatment during the recovery period after the demyelinating insult decreased remyelination and oligodendrogenesis. In addition, the demyelination-induced inflammation was decreased by lithium. Further studies are needed to investigate if those effects are specific for rats, the dose of lithium used and the brain region investigated. Studies from our laboratory have previously shown a low-grade glial cell activation following ECS. In paper III we show that blood-borne macrophages are recruited to the hippocampal vessel walls after ECS. It can represent the first step in an inflammatory process, but when no further signals are acquired further progression through the astrocytic end-feet layer into the brain parenchyma is halted. ECT’s clinical practice and general acceptance has been limited by concerns about side effects, particularly regarding memory deficits. Certain pharmacological agents administered in association with ECT may protect against amnesia. During recent years, lithium has been shown to reduce memory deficits induced by stroke, stress, head trauma etc. in rodents. In paper IV, we investigated the effect of ECS and lithium treatment on spatial memory and demonstrated robust memory loss for a hippocampus-dependent navigational task learned during the week preceding ECS. This finding was consistent in four independent investigations. However the effect of lithium treatment on ECS-induced amnesia was not as conclusive. In two identically designed studies, lithium counteracted the ECS-induced amnesia, but was neither associated with reduced cell death nor reduced microglia activation Importantly though, an anti-amnestic effect of lithium was not found in two following equally designed studies. Further investigations of ECS-related disturbances are currently ongoing in our research group.