Bipolar disorder (BD) is a severe and chronic psychiatric disorder that affects approximately 1-4% of the world population and is characterized by recurrent episodes of mania or hypomania and depression. BD is also associated with illnesses marked by immune activation, such as metabolic syndrome, obesity, type 2 diabetes mellitus, and cardiovascular diseases. Indeed, a connection has been suggested between neuroinflammation and peripheral inflammatory markers in the pathophysiology of BD, which can be associated with the modulation of many dysfunctional processes, including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. Rising evidence suggests that synaptic dysregulations, especially glutamatergic system dysfunction, are directly involved in mood disorders. It is becoming clear that dysregulations in connection and structural changes of glial cells play a central role in the BD pathophysiology. This book chapter highlighted the latest findings that support the theory of synaptic dysfunction in BD, providing an overview of the alterations in neurotransmitters release, astrocytic uptake, and receptor signaling, as well as the role of inflammation on glial cells in mood disorders. Particular emphasis is given to the alterations in presynaptic and postsynaptic neurons and glial cells, all cellular elements of the "tripartite synapse," compromising the neurotransmitters system, excitatory-inhibitory balance, and neurotrophic states of local networks in mood disorders. Together, these studies provide a foundation of knowledge about the exact role of the glial-neuronal interaction in mood disorders.