Understanding how individual neuronal subtypes contribute to neural network function is vital to understanding how the nervous system functions and in understanding how dysfunction of specific neuronal subtypes contributes to neurological and psychiatric diseases. However, current methods used to activate neurons or neuronal processes in intact nervous tissue have not permitted the indiscriminate excitation of an individual subtype of neuron. This proposal plans to develop a technique that will permit the selective activation of individual subtypes of neurons by expressing in specific types of neurons genes of proteins that are capable of depolarizing only those neurons when the activator protein is stimulated. The activator protein we will use is the snail FMRFamide ligand-gated sodium channel (FaNaC). FaNaC is ideal because it is not found in the mammalian nervous system thereby allowing selective activation of only the neurons in which it has been expressed. To improve this technique, we will attempt to synthesize a light-sensitive compound that can activate FaNaC expressing neurons with millisecond precision. Furthermore, we will use rapid activation of FaNaC or other heterologously-expressed proteins to study how specific types of inhibitory interneurons in hippocampal CA1 are controlled by specific types of surrounding neurons. Because inhibitory interneurons have roles in CNS diseases such as epilepsy, anxiety, schizophrenia and spasm, information obtained from these studies will be relevant to understanding how inhibitory interneuron dysfunction may contribute to abnormal CNS function.
This study proposes to develop a gene based tool that will permit the activation of specific types of neurons in intact nervous tissue. We plan to use this tool to examine the function of inhibitory interneurons in controlling hippocampal network activity. These studies will provide us with a model to understand the role of specific neurons in normal brain function and in psychiatric and neurological disorders.
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