A Critical Role of Presynaptic Cadherin/Catenin/p140Cap Complexes in Stabilizing Spines and Functional Synapses in the Neocortex

Abstract

The formation of functional synapses requires coordinated assembly of presynaptic transmitter release machinery and postsynaptic trafficking of functional receptors and scaffolds. Here, we demonstrate a critical role of presynaptic cadherin/catenin cell adhesion complexes in stabilizing functional synapses and spines in the developing neocortex. Importantly, presynaptic expression of stabilized β-catenin in either layer (L) 4 excitatory neurons or L2/3 pyramidal neurons significantly upregulated excitatory synaptic transmission and dendritic spine density in L2/3 pyramidal neurons, while its sparse postsynaptic expression in L2/3 neurons had no such effects. In addition, presynaptic β-catenin expression enhanced release probability of glutamatergic synapses. Newly identified β-catenin-interacting protein p140Cap is required in the presynaptic locus for mediating these effects. Together, our results demonstrate that cadherin/catenin complexes stabilize functional synapses and spines through anterograde signaling in the neocortex and provide important molecular evidence for a driving role of presynaptic components in spinogenesis in the neocortex.

Synaptic Elimination in Neurological Disorders

“…Throughout development, those spines that accumulate higher amounts of β-catenin/N-cadherin are preferably maintained and form stable spines, while those neighbor spines with lower levels of this protein complex are eliminated in an activity-dependent fashion [48]. These two proteins are also found pre-synaptically, functioning in the neocortex by stabilizing synapses and reducing their excessive turnover [49]. Despite having mentioned the main known mechanisms underlying synaptic pruning, additional mechanisms could also prove relevant (for more information on this topic, please refer to [1]).…”

The p140Cap adaptor protein as a molecular hub to block cancer aggressiveness

“…Vincenzo Salemme, Costanza Angelini, and Jennifer Chapelle contributed equally to this work as an interactor of SNAP-25 in the rat brain [1]. Its role in neurons was further evidenced by several groups, on account of the use of the p140Cap knock-out mouse model [8][9][10]. Subsequently, the human orthologue of rat SNIP proteins was identified by mass spectrometry in epithelial cells as the 140 kDa KIAA1684 protein indirectly associated with p130Cas through the last 217 amino acids of p140Cap and the amino acids 544-678 of p130Cas [3].…”

“…In addition to Src and Csk, p140Cap also binds to Betacatenin through the 351-1051 amino-acid portion [10]. The terminal proline-rich domain of p140Cap associates with Vinexin [16], and Cortactin, a Src kinase substrate and an F-actin-binding protein [8,35].…”

The development of local circuits in the neocortex: recent lessons from the mouse visual cortex

“…The authors proposed that methylation patterns influence the expression patterns of clustered protocadherins, cell adhesion molecules thought to play roles in self-recognition and non-self-recognition [47]. Other molecular mechanisms involved in input-specific regulation of synapse formation in primary somatosensory cortex may also contribute to circuit formation in V1 [43,48], as may mechanisms implicated in the regulation of synapse formation in specific cortical cell types and dendritic compartments [49–52]. Together, these studies demonstrate that, before visual experience, multiple mechanisms likely work in concert to establish early patterns of synaptic connections that generate initial receptive field properties — including the spatial structure, orientation tuning, and direction preference of mouse V1 neurons [41,46 •• ,53–55].…”

“…How the evolution of response properties during the first weeks following eye opening relates to underlying changes in synaptic connectivity remains unclear. Furthermore, the contributions of molecular mechanisms implicated in shaping synaptic connections in visual and somatosensory cortex in later development, including specifying connections among cortical neurons at the cell-type or subcellular levels, remains to be fully elucidated [48,50,62,63 •• ,64] (for reviews, see [65,66]). Nonetheless, together, these results indicate that experience-dependent, activity-dependent and activity-independent mechanisms contribute to cortical circuit development after eye opening.…”