Basic Mechanisms of Neuronal Development, Maintenance and Function in the Basal Ganglia

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Our research program aims at discovering how different areas of the mammalian brain acquire a precisely controlled complement of diverse types of nerve cells (neurons) and form the right connections. The developing nervous system generates far more neurons than can survive. Indeed, over half the neurons that are produced die by a form of programmed cell death known as apoptosis. A major factor determining which neuron subtypes survive is whether they are able to get adequate access to survival molecules known as neurotrophins. In order to acquire the correct neurotrophin, the nerve cell must express a receptor molecule, which recognizes the neurotrophin and facilities its survival action. Furthermore, it is preferable that nerve cells survive in response to some form of activity in their environment, allowing for a matching of activating input fivers, with the correct number and type of neurons to be ultimately available for healthy function of the adult nervous system.We propose that the neurotrophin brain-derived neurotrophic factor (BDNF) is produced by specific connecting inputs called axon terminals, which enter the target area of interest during the apoptosis period while neurons are still quite immature. These axons terminals release both activating neurotransmitters (e.g. glutamate) and BDNF in the vicinity of the vulnerable neurons. A cooperative action of the activating (depolarizing) transmsitter and BDNF results in survival of the target neurons provided it expresses the BDNF receptor. Once the connections between the incoming axon terminal and the neuron is established, the cooperative action of BDNF and glutamate is transformed into roles beyond survival, including neuron growth and finally participating of normal adult function. We focus of how this novel mechanism works in the striatum, a part of the brain that is crucial to normal movements. We propose that inputs to the striatum from the thalamus deliver glutamate and BDNF, which together allow BDNF receptor bearing neurons to survive. Ultimately, different inputs to the striatum depending on their chemical make-up, and when they arrive, may allow distinct subsets of neurons to survive. This input-mediated survival mechanism may be a major factor allowing for survival of precise subtypes of neurons which make up the adult brain.