Many neurological and psychiatric disorders are associated with aberrant neuronal activity, including depression, schizophrenia, and Alzheimer's disease. Abnormal neuronal activity impairs information processing within the brain, often interferes with learning and memory, and may lead to epilepsy. Neurons regulate their own activity in part by tightly controlling the expression of potassium ion channels. Selective pharmacological manipulation of these channels is severely limited due to structural similarities within these channels. The mRNA sequences encoding these channels have undergone greater divergence, however, and may be a viable therapeutic alternative. The expression of one particular voltage-gated potassium channel subunit known as Kv4.2 is tightly controlled at the level of mRNA translation. Kv4.2 mRNA is actively transported into neuronal dendrites where it is locally translated in response to synaptic signals. This process is regulated in part by the fragile x syndrome-associated protein FMRP, or fragile x mental retardation protein. Recent evidence suggests that FMRP does not act alone: FMRP likely regulates Kv4.2 mRNA translation in conjunction with microRNA activity. microRNAs (miRNAs) are small non-coding RNAs which bind to target mRNAs and interfere with their translation. Preliminary evidence indicates that the neuronal miRNA miR-324- 5p regulates Kv4.2 mRNA translation. The proposed research will explore the role of miR-324-5p activity in regulating Kv4.2 mRNA translation and surface expression specifically within dendrites (Specific Aim 1) using a combination of immunofluorescence and live cell imaging fluorescence microscopy applied to cultured hippocampal neurons. In addition, the proposed research will identify additional miRNAs that regulate Kv4.2 expression within neurons (Specific Aim 2) using a combination of bioinformatic predictions and biochemical validations in neuronal cultures and cell lines. Building from this foundation, future research may examine whether FMRP and miRNAs act cooperatively or antagonistically to regulate dendritic Kv4.2 expression and how these two mechanisms respond to synaptic signaling. By addressing these critical knowledge gaps, the proposed research may also serve as a foundation for novel therapeutic strategies that treat aberrant neuronal activity more effectively than the pharmacological tools currently in use.
Many common neurological and psychiatric disorders are associated with abnormal neuronal activity, including epilepsy, Alzheimer's disease, schizophrenia, and depression. We anticipate that this research will illuminate the mechanisms that neurons use to control their own activity and provide novel therapeutic targets for the treatment of these disorders.