The role of bioenergy sensing in neuronal polarization and synaptogenesis
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Abstract
Shortly after differentiation, neurons begin to abandon their symmetric shape as they polarize and establish two discrete functional domains--dendrites and axons. While dendrites contain post-synaptic receptors capable of responding to neurotransmitter released from upstream neurons, the axon is specialized for transmitter release in order to relay the information to downstream neurons. This unidirectional flow of information lays the ground work for all neural circuitry and allows complex organisms to detect, store and transmit information.
During the polarization process, axon initiation and subsequent rapid axonal outgrowth, requires large quantities of protein and membrane supplies. It is therefore logical that neurons closely couple the cellular energy level to accommodate enhanced growth. However, the role of energy regulatory pathways on neuronal polarization remains largely unknown. We therefore investigated the involvement of adenosine 5'monophosphate (AMP)-activated protein kinase (AMPK), the sole pathway regulating energy homeostasis in all eukaryotic cells. AMPK is activated by an elevated AMP/ATP (adenosine 5'-triphosphate) ratio when cellular energy becomes low and functions through the phosphorylation of downstream targets. We found that activation of the AMPK pathway suppressed axon initiation and neuronal polarization in a developmental stage dependent manner. Mechanistically, phosphorylation of the kinesin light chain of the kinesin I motor protein by AMPK disrupted the association of the motor with phosphatidylinositol 3-kinase (PI3K), preventing PI3K targeting to the axonal tip and inhibiting polarization and axon growth. We also demonstrated that under ischemia-caused energy lacking conditions, AMPK activation led to similar inhibition in neuronal polarization.
We next determined whether early acute AMPK activation could impart long-term effects on synaptogenesis in mature neurons. When AMPK was activated by ischemic challenges in early developing neurons, we found a significant reduction in pre- and post-synaptic protein expression and clustering after neuronal maturation, indicating a defect in synaptogenesis. The effect was also observed at the morphological level as dendrite growth and spine maturation were markedly inhibited. These results represent important implications in our understanding of neuron development, neural, network formation and the pathogenesis of neurological diseases.
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Thesis (Ph.D.)--Boston University
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