Dopaminergic Modulation of Dendritic Excitability

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Schizophrenia is a mental disorder with devastating symptoms, yet, at the macroscopic level, the brains of schizophrenics are no different than the brains of healthy subjects. Recent electron microscope studies, however, revealed microscopic structural abnormalities that affect the dendrites of neocortical pyramidal neurons. Interestingly, distal parts of these dendrites of pyramidal cells are targets of dopaminergic axon terminals. Furthermore, in prefrontal cortex, an area implicated in pathophysiology of schizophrenia, individual dendritic spines are occupied by two presynaptic terminals; one axon terminal that secretes excitatory transmitter (glutamate), and the other one that secretes dopamine. It is thought that dopamine secretion is elevated in schizophrenia because dopamine receptor blockers alleviate some symptoms. Our working hypothesis is that abnormally high dopamine secretion suppresses dendritic excitability and severely disrupts information processing at the level of individual neurons (a process also know as integration of synaptic inputs). In the laboratory, we are mimicking the arrival of glutamatergic and dopaminergic inputs by delivering glutamate and dopamine pulses locally, onto individual dendritic branches (local application of neurotransmitters through glass pipettes). This approach allows precise control of the location of excitatory input to the dendritic tree, with precise timing, and most importantly, the role of presynaptic mechanisms in the interpretation of experimental results is eliminated. With the help of voltage-sensitive dyes, the effects of dopamine on dendritic membrane potential will be analyzed simultaneously at the glutamate stimulation site, as well as in the neighboring dendrites that are exposed to neither glutamate nor dopamine. The proposed experiments are expected to yield a more complete picture of how local fluctuation in dopamine level can shape the information processing in individual neurons, and provide impetus for new therapeutic approaches in schizophrenia.