Synapsins were the first presynaptic proteins identified and have served as the flagship of the presynaptic protein field. Here we review recent studies demonstrating that different members of the synapsin family play different roles at presynaptic terminals employing different types of synaptic vesicles. The structural underpinnings for these functions are just beginning to be understood and should provide a focus for future efforts.

Subsynaptic structures such as bouton, active zone, postsynaptic density (PSD) and dendritic spine, are highly correlated in their dimensions and also correlate with synapse strength. Why this is so and how such correlations are maintained during synaptic plasticity remains poorly understood. We induced spine enlargement by two-photon glutamate uncaging and examined the relationship between spine, PSD, and bouton size by two-photon time-lapse imaging and electron microscopy. In enlarged spines the PSD-associated protein Homer1c increased rapidly, whereas the PSD protein PSD-95 increased with a delay and only in cases of persistent spine enlargement. In the case of nonpersistent spine enlargement, the PSD proteins remained unchanged or returned to their original level. The ultrastructure at persistently enlarged spines displayed matching dimensions of spine, PSD, and bouton, indicating their correlated enlargement. This supports a model in which balancing of synaptic structures is a hallmark for the stabilization of structural modifications during synaptic plasticity.

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP-mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.

Studies of brain network connectivity improved understanding on brain changes and adaptation in response to different pathologies. Synaptic plasticity, the ability of neurons to modify their connections, is involved in brain network remodeling following different types of brain damage (e.g., vascular, neurodegenerative, inflammatory). Although synaptic plasticity mechanisms have been extensively elucidated, how neural plasticity can shape network organization is far from being completely understood. Similarities existing between synaptic plasticity and principles governing brain network organization could be helpful to define brain network properties and reorganization profiles after damage. In this review, we discuss how different forms of synaptic plasticity, including homeostatic and anti-homeostatic mechanisms, could be directly involved in generating specific brain network characteristics. We propose that long-term potentiation could represent the neurophysiological basis for the formation of highly connected nodes (hubs). Conversely, homeostatic plasticity may contribute to stabilize network activity preventing poor and excessive connectivity in the peripheral nodes. In addition, synaptic plasticity dysfunction may drive brain network disruption in neuropsychiatric conditions such as Alzheimer's disease and schizophrenia. Optimal network architecture, characterized by efficient information processing and resilience, and reorganization after damage strictly depend on the balance between these forms of plasticity.