Learning and memory are dynamic processes that require alterations in the connections among neurons. Synapses, the structures through which neurons communicate with one another, undergo biochemical and morphological changes in response to neuronal activity in a process known as synaptic plasticity. Disturbed synaptic plasticity is the basis for several diseases such as dementia, schizophrenia, and Alzheimer's disease. Local translation of mRNAs in dendrites is essential for regulating certain forms of synaptic plasticity. Impairment of this process is the cause of several neuropathies such as the Fragile-X Syndrome and other disorders linked to autism. Modulation of cytoplasmic mRNA poly(A) tail length is one mechanism that controls local translation in dendrites. It is estimated that ~7% of brain RNAs are regulated by this process in response to stimulation, which underscores its importance in synaptic plasticity and therefore higher cognitive function. Because poly(A) tails lengthen as well as shorten, there are likely to be several enzymes involved in this process. Several factors responsible for poly(A) elongation have been identified, but the enzyme(s) responsible for shortening the poly(A) tail remains unknown. The proposed research seeks to identify this deadenylating enzyme, which is likely to act as a negative regulator of dendritic translation and learning and memory. The proposed research focuses on CNOT7, a major mammalian deadenylase, in the brain and seeks to test whether (1) knockdown or mutation of CNOT7 alters poly(A) tails in cultured neuronal dendrites, (2) CNOT7 controls specific mRNA deadenylation in dendrites, and (3) knockdown of CNOT7 alters various forms of synaptic plasticity. This work will further our understanding of the process of learning and memory and disorders affecting these important processes.
Impairment of local translation in neurons affects learning and memory and has been linked to several disorders such as autism, dementia, and Alzheimer's Disease. The proposed research seeks to identify an important negative regulator of local translation in neurons and learning and memory. The identification of this important enzyme will improve the treatment of disorders affecting learning and memory by furthering the understanding of these disorders.
|McFleder, Rhonda L; Mansur, Fernanda; Richter, Joel D (2017) Dynamic Control of Dendritic mRNA Expression by CNOT7 Regulates Synaptic Efficacy and Higher Cognitive Function. Cell Rep 20:683-696|