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

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.