Dopaminergic modulation of dentritic excitability

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Medical drugs used in treatment of schizophrenia or depression exert their action through the modulation of dopaminergic neurotransmission. The exact mechanism of such therapy is unknown, partly because the normal physiological role of dopamine release in the cortex is also not fully understood. Electron microscope studies, performed postmortem on the brains of people who suffered from schizophrenia, revealed microscopic structural abnormalities that affect the dendrites of cortical pyramidal neurons. Changes in cortical thickness and dendritic ultrastructure, detected postmortem, could be due to a very long (lifetime) duration of the mental illness and/or a very long (chronic) drug therapy. However, recent clinical studies revealed clear changes in grey matter volume in schizophrenic patients at the very onset of the disease; during the transition from pre-psychotic to psychotic phase. What is the causal relation between the efficacy of dopaminergic drugs, and impairment in dendritic structure and function? The answer to this question may lie in the anatomical juxtaposition of the glutamatergic and dopaminergic systems in the frontal part of human brain, responsible for cognition, planning, control of emotions and decision making. In the prefrontal cortex (an area strongly implicated in pathophysiology of schizophrenia) individual dendritic spines are occupied by two presynaptic terminals; one axon terminal that secretes the excitatory transmitter (glutamate), and the other one that secretes modulatory transmitter dopamine. Twenty years after the discovery of direct dopamine synapse onto a cortical pyramidal neuron, the exact functional consequence of dopamine release at the postsynaptic membrane, in distal dendrites, is still unknown. In the laboratory, we are mimicking the arrival of glutamatergic and dopaminergic cortical inputs by combining excitatory synaptic stimulation of individual dendritic branches with local application of dopamine through a glass micropipette. This approach allows precise control of the location of excitatory input in the dendritic tree; precise timing and duration. Local applications of exogenous glutamate and dopamine eliminate presynaptic mechanisms in the interpretation of experimental results. With the help of voltage-sensitive dyes, the effects of dopamine on dendritic membrane potential will be analyzed simultaneously at the synaptic 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 fluctuations in dopamine level can shape integration of signals in individual neurons, and provide impetus for new preventive and therapeutic approaches in treatment of psychiatric disorders associated with dopaminergic dysfunction.