Presumably, an BEZ235 increased interaction between a-actinin-2 and actin filament bundles recruits additional actin bundles in the spine. Increased actin cross-linking could also serve to cluster the myriad of PDZ- and LIM-containing proteins in the PSD, recruit other actin-binding proteins to the PSD and thereby promote its enlargement. An additional mechanism for recruitment of PSD molecules to the spine via a-actinin-2 could occur through its putative binding interactions with components of the PSD, including densin-180, CaMKIIa, and the NR1 and NR2B subunits of the NMDA-type glutamate receptor. Therefore, a-actinin-2 may nucleate assembly and growth of the PSD through direct recruitment of PSD molecules, and connect these proteins to actin filaments. It is possible that increased stability of the PSD, which reinforces trans-synaptic connections, is required for spine maturation. Some observations support this hypothesis. Spines lacking a-actinin-2 do not appose excitatory, pre-synaptic boutons, as shown by the lack of VGLUT1 and FM4-64 juxtaposed to these immature spines. The absence of a functional synapse illustrates why glycine stimulation is insufficient in driving maturation of spines deficient in a-actinin-2. Both knockdown and overexpression of a-actinin-2 induce similar phenotypes, consisting of an immature spine morphology lacking an organized PSD. Neurons deficient in a-actinin-2 have diminished actin filament bundles in their spines, whereas overexpression of a-actinin-2 in neurons likely creates spines with overly cross-linked actin filaments. Others have reported analogous observations. Knockout of the gene encoding the actin crosslinker protein spinophilin/neurabin II increased spine density in vivo and the number of filopodia-like protrusions in cultured neurons. Furthermore, overexpression of other actin crosslinkers, including drebrin and a non-contractile myosin IIB mutant, increased spine length and the number of immature dendritic protrusions. These findings suggest that a fine balance of actin filament bundling in the spine is necessary to drive proper synapse maturation and spine morphology. PP2A participates in various pathways controlling metabolism, DNA replication, transcription, RNA splicing, translation, cell cycle progression, morphogenesis, development and transformation. To target a broad range of cellular substrates with sufficient specificity, PP2A assembles into diverse trimeric holoenzymes. Each holoenzyme consists of a common core formed by the scaffolding and the catalytic subunit and associates with a variable regulatory B-subunit into a heterotrimeric complex. Four families of regulatory Bsubunits, with no homology between them and very different expression levels in different cell types and tissues have been identified to date: B/B55/PR55,B56/PR61, PR72/PR70 and Striatin/PR93. Within the holoenzyme, the regulatory B-subunits control the function of PP2A by mediating substrate specificity and modulating the catalytic activity.