CNR - Institute of Neuroscience CNR
Institute of Neuroscience


Cellular and molecular mechanisms of synaptic plasticity

A basic question in neurobiology is how neuronal activity causes long lasting changes in synaptic structure and function that may contribute to learning and memory. Synapses are the sites of most information processing in the brain, and changes in the molecular composition of the postsynaptic compartment are likely critical for the modulation of synaptic efficacy in normal and pathological conditions. My laboratory is interested in understanding the functions of proteins which regulate synapses formation and plasticity.

The Shank family of protein

The postsynaptic density (PSD) consists of a network of interacting proteins that form an electron-dense organelle right beneath the postsynaptic membrane. Most PSD proteins function as scaffolds that anchor and link glutamate receptors and other postsynaptic membrane proteins to cytoskeletal elements and signaling pathways. Shank families of proteins are among some of the major scaffold proteins that organize the PSD. Shank1-3 proteins are large scaffold proteins that contain ankyrin repeats, an SH3 domain, a PDZ domain, a proline-rich domain and a SAM domain. They are associated with the NMDA receptor-PSD-95 complex by their binding to C-terminal GKAP, and with type I mGluRs via an interaction with Homer in the proline-rich domain. A number of actin regulatory molecules bind to Shank in the proline-rich domain (cortactin, IRSp53, and AbP1), or in the PDZ domains, (beta-PIX).

It is also known that the overexpression of Shank1 and Homer in hippocampal cultures induces synapse maturation associated with the enlargement of dendritic spines (Sala et al., 2001). These data suggest that Shank acts as a major scaffold for postsynaptic proteins and as a molecular bridge linking multiple glutamate receptor subtypes to the postsynaptic cytoskeleton. The important role of Shank in synapse function is also supported by the finding that in humans mutations or haploinsufficiency of Shank3, found in the 22q13 deletion syndrome, causes mental retardation and autism.

In the last few years we have contributed in showing that

  1. stability and targeting to synapses depend on the interaction with GKAP/SAPAP and PSD-95, also because the dissociation of PSD-95 from this complex induces the degradation of Shank and GKAP (Romorini et al, 2004);
  2. Shank1 promotes the accumulation of postsynaptic density proteins, such as GKAP and NR1, in dendritic spines, it increases the F-actin content and recruits functional sER compartments in spines (Sala et al., 2003; Sala et al, 2005);
  3. Homer and Shank form a mesh-like matrix structure in the PSD that works as an assembly platform for other PSD proteins (Hayashi et al 2009).

For Shank3 we have shown that its overexpression in cerebellum granule cells induces dendritic spine and synapse formation by recruiting different subtypes of glutamate receptors, whereas the inhibition of Shank3 expression in hippocampal neurons reduces the number of dendritic spines (Roussignol et al, 2005). Interestingly in Shank3 knock down neurons the mGluR signalling at synapse is specifically altered.

We also showed that the three SHANK genes possess several methylated CpG boxes, but only SHANK3 CpG islands are highly methylated in tissues where protein expression is low or absent and unmethylated where expression is present. These findings suggest the possibility to regulate the expression of Shank3 pharmacologically and open the possibility of a therapy for the 22q13 deletion syndrome.

The role of Shank3 mutation in causing mental retardation has stimulated the study of other synaptic genes whose mutations have been demonstrated to be causing mental retardation, even if the molecular function of these proteins has not been demonstrated.

Identification of molecular mechanisms regulating synaptic plasticity


We have used a proteomic approache to reveal changes in protein synthesis, degradation and post-transalational modifications in rat hyppocampal neurons during synaptic activity. Using these approaches we have identified about sixty proteins whose expression and/or post-translational modifications were altered by synaptic activity. These proteins regulate a variety of cellular processes including protein and energy metabolism, and cytoskeletal and mitochondrial function (Piccoli et al. 2007). We are currently studing the function of some of these proteins in regulating activity dependent remodelling of synapses structure and dendritic spines.


  • Hayashi MK, Tang C, Verpelli C, Narayanan R, Stearns MH, Xu RM, Li H, Sala C, Hayashi Y (2009) The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137:159-71.
  • Piccoli G, Verpelli C, Tonna N, Romorini S, Alessio M, Nairn AC, Bachi A, Sala C (2007) Proteomic analysis of activity-dependent synaptic plasticity in hippocampal neurons. J. Proteome Res. 6:3203-15.
  • Gerrow K, Romorini S, Nabi SM, Colicos MA, Sala C, El-Husseini A (2006) A preformed complex of postsynaptic proteins is involved in excitatory synapse development. Neuron 49:547-62.
  • Sala C, Roussignol G, Meldolesi J, Fagni L (2005) Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons. J. Neurosci. 25:4587-92.
  • Romorini S, Piccoli G, Jiang M, Grossano P, Tonna N, Passafaro M, Zhang M, Sala C (2004) A functional role of postsynaptic density-95-guanylate kinase-associated protein complex in regulating Shank assembly and stability to synapses. J. Neurosci. 24:9391-404.
  • Sala C, Futai K, Yamamoto K, Worley PF, Hayashi Y, Sheng M (2003) Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a. J. Neurosci. 23:6327-37.


Telethon Italia, 2006-2008 coordinator

Fondazione Cariplo, 2007-2009 coordinator

Compagnia San Paolo, 2008-2009 partner

RSTL CNR, 2008-2009 coordinator

Italian Ministry of University and Scientific Research, PRIN 2007, 2008-2009 partner


  • P. Billuart, Institut Cochin, Paris, Francia.
  • L. Fagni, CNRS UPR 9023, Montpellier, Francia.
  • Y. Hayashi, RIKEN-MIT Neuroscience Research Center, The Picower Center for Learning and Memory, Massachusetts Institute of Technology, Cambridge, USA.
  • C. Bonaglia, R. Giorda, Scientific Institute Scientifico "E. Medea", IRCCS, Bosisio Parini (LC), Italy.


PI photo

Carlo Sala

Contact information

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email  +39 02 5031 7096

Participating staff