Regulatory effects of orexin A on neuronal networks formation and activity in vitro

Orexin A (OXA) is a neuropeptide, isolated from neurons in the hypothalamus, which regulates various brain activities, including wakefulness and higher brain functions like learning and memory. There is a growing interest in OXA’s role in neurodegenerative diseases with respect to non-motor symptoms such as sleep-, attention- and cognitive- disorders. Recent studies in Parkinson’s and Alzheimer’s patients found lower concentrations of OXA in the prefrontal cortex and cerebro-spinal fluid. It is widely assumed that deteriorated cognitive processes are related to impaired network connectivity. However, little is known about the effects of OXA on the network activity and synaptogenesis. Therefore, we investigated the development of activity in dissociated cortical neurons of rat chronically treated with 0.5 µM OXA for three weeks. Network activity was recorded with multi electrode arrays. Additionally, after one-, two- or three weeks cultures were stained immunocytochemically for detection of the presynaptic marker synaptophysin. OXA treated cultures become spontaneously active earlier, and the plateau of their activity was higher than in controls. Immunostaining revealed that the synaptic density was much higher in OXA treated cultures in all age groups. Hence, OXA has a strong stimulating effect on network formation and activity, the latter probably being a consequence of the accelerated synaptogenesis. These results indicate that drugs, based on OXA are potential candidates for prevention and treatment of disorders associated with neuronal connectivity and activity decline.