**Acknowledgements**

The above results are consist with a model (**Figure 5**) in which (1) the expression of functional plasticity (LTP) and structural plasticity (spine enlargement) are initially two independent processes only share the activation of NMDARs; (2) these two processes then enter an interactive state that the continuous presence of one is required for the persistence of the other; (3) the above state is liable in that interference (such as low frequency stimulation) can revert both changes back to the baseline; (4) once both processes are stabilized, synapse modification has entered a state resistant to reversal. We like to note that during the "grace period" coordinated changes in synaptic plasticity (function and structure) are cross-checked to ensure that they do occur together, and in the situation only one such process occurs (perhaps can be viewed as a mistake), the other process will be aborted albeit in process. This double-proof mechanism is essential to ensure that only appropriate changes are allowed to be sustained, and may thus be especially important in face of the highly dynamic nature of synaptic modi-

Sustained reduction in synaptic strength may eventually lead to the loss of synaptic connections, and this loss is manifested as a reduction in spine density. Spine loss appears to be a protracted process and hence it is difficult to study. Even if monitoring changes in the same set of synapses/spines, it is usually more difficult to exclude the possibility that the reduced synaptic function and spine number is caused by deterioration of the health of the preparation, or by some other unknown or uncontrolled processes that occur randomly during the long period (>hours) between LTD induction and spine loss. Nonetheless, a few studies have examined this process. By using organotypical slices and monitoring both presynaptic boutons and spines, Becker et al. showed that LTD induction increased the turnover rate of presynaptic boutons and resulted in decreased synaptic contacts between the pre- and post-synaptic sites. Although presynaptic boutons and postsynaptic spines disappear at much greater rate after LTD, there is no particular pattern to follow, since disappearance of either presynaptic boutons or spines could occur prior to the other [97]. Therefore, the above observations suggest that the mismatch between presynaptic and postsynaptic sites is more likely a key factor in the elimination of synapse, while the exact sequence might not

Dendritic spines are small protrusions on the dendritic shaft as major excitatory inputs site on the excitatory neurons in the adult cortex. Spines play critical roles in the excitatory synaptic transmission and plasticity. Genesis of spines occurs during brain development, and is subjected to activity-dependent modulation to determine their fates, either to transit to mature spines or be eliminated. Spines are the site where physiological/functional and morphological/structural modifications meet and integrate, during both physiological (such as memory formation) and pathological (such as neurodegeneration) processes. Interestingly, early changes in functional and structural aspects of synapse modification occur independently, but they subsequently interact with each other to sustain changes in both. This highly interactive nature ensures that the end result is a coherent modification of synapse function

fications, such as those occurring during early neural development [94].

158 Neuroplasticity - Insights of Neural Reorganization

play much role.

**5. Conclusions**

This work was supported by grants from Peking University Shenzhen Graduate School and grants from Shenzhen government (ZDSYS201504301539161 and KQTD2015032709315529).
