Glutamate-Dependent Regulation of Acetylcholine Activity

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Neurons communicate with each other through chemical substances, neurotransmitters. Glutamate is the predominant fast excitatory neurotransmitter in the central nervous system (CNS) that is secreted by some neurons and activates other neurons. A decreased level of glutamate activity can be found in the CNS during embryonic development and during some pathological conditions. Recent studies indicate that during a long-term decrease in glutamate activity, the activity of another less predominant excitatory neurotransmitter, acetylcholine (ACh), is dramatically increased. It was hypothesized that in the absence of glutamate, ACh plays the role of the major excitatory neurotransmitter in some regions of the CNS. However, the mechanisms that increase ACh activity when glutamate activity is decreased have not yet been studied. They will be studied in the proposed research. Using neuronal cultures obtained from the hypothalamic region of the brain, two hypotheses will be tested. The first hypothesis is that during a decrease in glutamate activity neurons that secrete glutamate change their phenotype and begin to secrete ACh. The second hypothesis is that the change in phenotype is due to the decrease in Ca2+ influx to the neurons and the inactivation of certain intracellular Ca2+ signaling pathways. Since glutamate is a major excitatory neurotransmitter in the CNS and is involved in many functions of the brain, it is very important to know the mechanisms that regulate the functions of neuronal networks when glutamate activity is decreased. Increased ACh transmission is likely one of such mechanisms. This project addresses the investigation of the fundamental mechanisms of neuronal plasticity and the regulation of neuronal activity that can take place in neuronal circuits during a decrease in glutamate excitation.