Imbalance of Glial-Neuronal Interaction in Synapses: A Possible Mechanism of the Pathophysiology of Bipolar Disorder

There is a wave of new information suggesting that glia, especially astrocytes, are intimately involved in the active control of neuronal activity and synaptic transmission. Synaptically associated astrocytes should be viewed as integral modulatory elements of tripartite synapses consisting of the presynapse, the postsynapse, and the glial element (astrocytes). Smit and coworkers proposed a model of a cholinergic tripartite synapse based on the identification of a glial-derived binding protein (BP) that is secreted into the synapse and binds free acetylcholine (ACh), thus reducing the levels of ACh available for stimulating the postsynapse. Here the author proposes an explanatory model of the pathophysiology of bipolar disorder focusing on the possible dynamics in cholinergic tripartite synapses. The hypothesis is that an imbalance between neurotransmitters and glial BPs in the synaptic cleft is determined by glia. If glial BPs are overexpressed, synaptic transmission is suppressed because of reduced levels of bioavailable neurotransmitters. This state could cause a depression on the behavioral level. In contrast, if glial BPs are underexpressed, the excess of neurotransmitters in the cleft leads to an overbalanced state of synaptic information transmission. This state could cause manic behavior. Under certain conditions, underbalanced and overbalanced synapses at different locations in the same brain could disturb brain function in parallel causing a mixed episode of bipolar disorder. If glial BPs and mutations in genes expressing glial BPs in the various synapses of the brain are identified, this hypothesis can be experimentally tested.