Key Mechanisms Regulating Synaptic and Cell Wide Forms of Homeostatic Plasticity.

Homeostatic Plasticity;BDNF;Proteasome;Neurosciences;Health Sciences;Neuroscience

Jakawich, Sonya Kee YunUmemori, Hisashi ;

University of Michigan

关键词: Homeostatic Plasticity;    BDNF;    Proteasome;    Neurosciences;    Health Sciences;    Neuroscience;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/84493/jakawich_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Sustained alterations in neuron activity elicit compensatory changes in synaptic function, a form of adaptation known as homeostatic plasticity.Homeostatic forms of plasticity are thought to maintain neural circuit activity within a dynamic, yet stable, functional range in the face of potentially destabilizing environmental influences.In recent years, homeostatic plasticity has received considerable attention as its dysregulation may lead to instability of neuronal circuits which, in turn, may contribute to the development of neurological disorders such as epilepsy.Typically, sustained changes in network activity drive a slow form of homeostatic plasticity that emerges over an 18-24 hr period. However, neurons also exhibit homeostatic adaptations that emerge 1-3 hr following direct disruption of synaptic activity, suggesting that separate slow and rapid forms of homeostatic plasticity exist at synapses.Both slow and rapid forms of homeostatic plasticity can emerge as changes in presynaptic neurotransmitter release(presynaptic compensation) or in the abundance of postsynaptic neurotransmitter receptors (postsynaptic compensation).However, the molecular mechanisms underlying these unique slow and rapid forms of homeostatic plasticity remain largely unknown.Here, key molecular events underlying these homeostatic forms of regulation are elucidated. Slow homeostatic plasticity requires targeted protein degradation by the postsynaptic ubiquitin proteasome system (UPS). Postsynaptic blockade of the UPS can both mimic and occlude slow homeostatic plasticity expression mechanisms suggesting that network driven changes in activity engage proteasome function to drive slow homeostatic adaptations at synapses. In contrast, rapid homeostatic plasticity requires presynaptic UPS function. Rapid homeostatic plasticity mechanisms require coupling of presynaptic UPS function with postsynaptic protein translation, retrograde synaptic signaling by BDNF/TrkB and the presence of presynaptic action potential activity. Together, these results demonstrate that slow (disruption of network activity) and rapid (disruption of synaptic activity) forms of homeostatic plasticity require unique pre- and post- synaptic mechanisms that additionally work together to coordinate expression of pre- and post- synaptic functional compensation. Understanding key molecular components underlying homeostatic plasticity mechanisms may lead to an advanced understanding of destabilizing neurological disorders, such as epilepsy.