Bipolar Disorder as a neuroplasticity disorder

Abstract

Bipolar Disorder (BD) is a chronic and recurrent mood disorder characterized by alternating episodes of depression and mania. BD, or manic depression, causes fluctuations in mood, energy, and functioning. These changes may be subtle or dramatic and although significant progress in experimental research has been made in the last years with numerous genetic association studies aiming at identifying susceptibility genes for BD, the exact neurobiological substrate of the disease as well as the therapeutic mechanisms of action of mood stabilizers have not been yet clarified. The observed heterogeneity in the symptomatology of bipolar patients as well as the total lack of animal models that reflect the full spectrum of the bipolar symptomatology constitute a major obstacle in the understanding of the pathophysiology of BD and the development of novel pharmacotherapies. Current theories support the notion that mood disorders, which are highly linked to a genetic background as evidenced with family, twin and adoption studies, could be better conceptualized in the general context of neuroplasticity disorders, indicating that these disorders are rather related to disturbances in complex intracellular signaling cascades and synaptic plasticity than to a simple disturbance of a single neurotransmitter system. Disturbances in the level of signal transduction within the nerve cell and between nerve cells as well as structural and functional changes constitute different levels of neuronal plasticity that seem to be affected in individuals with BD. The present paper is a comprehensive review of findings summarizing deficits in multiple levels of neuronal plasticity in BD and emphasizes dysfunctions in multiple levels of several intracellular signaling cascades. Deficits in multiple levels in the signaling pathway of cyclic adenosine monophosphate (cAMP), phospholipid and arachidonic acid metabolism, Ca2+/calmodulin-dependent protein kinase (CaMK), glycogen synthase kinase 3 (GSK3), extracellular signal regulated kinase (ERK) and neurotrophins cascade might be related to the pathophysiology of the disease. In addition to the changes in intracellular signaling, bipolar patients exhibit disturbances in the cells of the Central Nervous System (CNS) and particularly in the morphology of neurons and glia, which are reflected as structural and functional deficits of major brain regions involved in mood regulation. According to these findings, BD is characterized by several neuronal plasticity deficits in multiple physiological levels. Thus, disturbances in critical neuronal circuits which are involved in the regulation of emotions could result in the related symptomatology and the typical cycle of depressive and manic episodes. In conclusion, current research demonstrates that the neuronal circuits of bipolar patients exhibit deficits in their ability to change and adapt. Moreover, these deficits are likely to give rise to the underlying symptoms and the characteristic alternation of manic and depressive episodes.