Colocalization of Neurotransmitters in Hippocampus and Afferent Systems: Possible Functional Role

In neurophysiology, the transmitter phenotype is considered as an indicator of neuronal identity. It has become known at the end of last century that a nerve cell can produce and use several different molecules to communicate with other neurons. These could be "classical" transmitters: glutamate or gamma-aminobutyric acid (or acetylcholine, serotonin, norepinephrine), as well as secondary messengers, mainly neuropeptides released from the same neurons. In the case, when classical neurotransmitters are released together from the same nerve cell, this event is called cotransmission or corelease (release from the same vesicles). In this review article, the term "cotransmission" is used in a broad sense, denoting neurons that can release more than one classical mediator. Since transmitters are often intermediate products of metabolism and are found in many cells, the neuron classification is currently based on the carrier proteins (transporters) that "pack" neurotransmitters synthesized in the cytoplasm into vesicles. Here, we limit the issue of colocalization of the main neurotransmitters in mammals to the neurons of hippocampus and those structures that send their pathways to it. The review considers problems concerning the mechanisms of multitransmitter signaling, as well as probable functional role of mediator colocalization in the work of hippocampus, which yet has been poorly understood. It has been suggested that co-expression of different mediator phenotypes is involved in maintaining the balance of excitation and inhibition in different regions of hippocampus, facilitates rapid selection of information processing mode, induction of long-term potentiation, maintenance of spatial coding by place cells, as well as ensuring flexibility of learning and formation of working memory. However, the functional role of mediator colocalization, as well as the mechanisms of release of "dual" transmitters, have not been fully elucidated. The solution of these problems will advance some areas of fundamental neuroscience and help in the treatment of those diseases, where disruption of the balance between excitation and inhibition is detected, such as, for example, in epilepsy, Alzheimer's disease, and many others.