Neuromodulator Actions in Prefrontal Cortical Neurons

DESCRIPTION (provided by applicant): Dysfunction of the mesocortical neurotransmitter systems has been implicated in many neurological and mental disorders, including schizophrenia, depression and anxiety. Increasing evidence has suggested that many of these diseases result from altered serotonergic pathways and their dysregulation of neuronal activity in prefrontal cortex (PFC), a critical brain region controlling cognition and emotion. Many novel antipsychotic agents, antidepressants and anxiolytics act on serotonin receptors in PFC neurons. Understanding molecular and cellular mechanisms underlying the actions of serotonin in PFC is crucial for designing more effective therapeutic strategies in the treatment of brain disorders. Despite considerable progress on understanding the significance of serotonin at the system level, how serotonin regulates cellular excitability and synaptic function of PFC neurons remains unclear. It is our long-term goal to understand the molecular and cellular mechanisms of serotonin signaling in prefrontal cortex. Serotonin exerts its actions mainly through a complex set of G protein-coupled receptors. PFC is composed of glutamatergic pyramidal neurons and GABAergic interneurons. AMPA-type glutamate receptors and GABAA receptors, both of which contain intrinsic ion channels, are major players mediating excitatory and inhibitory synaptic transmission respectively in PFC. It is my working hypothesis that GABAA receptor channels and AMPA receptor channels are two major targets of the serotonin system. Serotonin plays a pivotal role in the regulation of PFC functions by suppressing GABAergic inhibitory activity and potentiating counterbalancing glutamatergic neurotransmission in PFC neurons through different 5-HT receptor-mediated signaling cascades. To characterize the signal transduction mechanisms underlying the serotonergic modulation of these channels in PFC neurons, a combination of electrophysiological, pharmacological and molecular approaches will be used. The coordinated expression and subcellular localization of serotonin receptors in PFC neurons will be determined using single-cell mRNA profiling and immunocytochemistry methods. The effect of serotonin on the biophysical properties of GABAA and AMPA receptor channels will be studied using patch-clamp analyses of PFC neurons. The intracellular signaling pathways utilized by serotonin to modulate these channels will be revealed using pharmacological tools, molecular and biochemical assays. This study will provide important insights into the molecular and cellular mechanisms underlying serotonergic regulation of cellular activity and synaptic transmission in PFC neurons. Knowledge gained from this work would contribute to the development of novel therapeutic strategies for many neurological and mental disorders.