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Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation.

ABSTRACT: In response to decreased activity, neurons make global compensatory increases in excitatory synaptic strength. However, how neuronal maturity affects this process is unclear. We silenced cultured hippocampal neurons with TTX at 7 days in vitro, during rapid synaptogenesis, and at 14 days, when major synaptogenesis is complete. For each age, we have explored the effects of short (1 day) and longer (2 days) periods of silencing. We have confirmed that the changes in synaptic strength depend on 2 main mechanisms, one presynaptic and the other postsynaptic. The presynaptic mechanism involves an increase in the probability of neurotransmitter release, mostly arising through an increase in the number of synaptic vesicles available for release. The postsynaptic mechanism operates through an increase in the number of postsynaptic receptors for the excitatory neurotransmitter glutamate. When neurons are silenced for 1 day, young neurons employ the postsynaptic mechanism, whereas more mature neurons increase their strength through the presynaptic mechanism. The postsynaptic strengthening in young neurons does not depend on gene transcription, whereas the presynaptic mechanism does. If neurons are silenced for 2 days, younger and older neurons employ both pre and postsynaptic mechanisms for synaptic strengthening. We also found evidence for 2 additional mechanisms that increased the effective synaptic coupling between neurons after 2 days of silencing: an increase in the number of synapses, and an increase in the electrotonic length of dendrites. These results expand our basic understanding of neuronal homeostasis, and reveal the developmental regulation of its expression mechanisms.

SUBMITTER: Han EB

PROVIDER: S-EPMC2705571 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation.

Han Edward B EB Stevens Charles F CF

Proceedings of the National Academy of Sciences of the United States of America 20090609 26

In response to decreased activity, neurons make global compensatory increases in excitatory synaptic strength. However, how neuronal maturity affects this process is unclear. We silenced cultured hippocampal neurons with TTX at 7 days in vitro, during rapid synaptogenesis, and at 14 days, when major synaptogenesis is complete. For each age, we have explored the effects of short (1 day) and longer (2 days) periods of silencing. We have confirmed that the changes in synaptic strength depend on 2 m ...[more]

PMID: 19509338

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Project description:Copy number variations encompassing the gene encoding Cyfip1 have been associated with a variety of human diseases, including autism and schizophrenia. Here we show that juvenile mice hemizygous for Cyfip1 have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reduced Cyfip1 levels serve to decrease paired pulse facilitation and increase miniature EPSC frequency without a change in amplitude. Higher-resolution examination shows these changes to be caused primarily by an increase in presynaptic terminal size and enhanced vesicle release probability. Short hairpin-mediated knockdown of Cyfip1 coupled with expression of mutant Cyfip1 proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role for Cyfip1 in the generation of normally functioning synapses and suggest a means by which changes in Cyfip1 levels could impact the generation of neural networks and contribute to abnormal and maladaptive behaviors.Significance statementSeveral developmental brain disorders have been associated with gene duplications and deletions that serve to increase or decrease levels of encoded proteins. Cyfip1 is one such protein, but the role it plays in brain development is poorly understood. We asked whether decreased Cyfip1 levels altered the function of developing synapses. The data show that synapses with reduced Cyfip1 are larger and release neurotransmitter more rapidly. These effects are due to Cyfip1's role in actin polymerization and are reversed by expression of a Cyfip1 mutant protein retaining actin regulatory function or by inhibiting Rac1. Thus, Cyfip1 has a more prominent early role regulating presynaptic activity during a stage of development when activity helps to define neural pathways.

Dataset Information

Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation.

Publications

Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation.

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