CNR - Institute of Neuroscience CNR
Institute of Neuroscience


Cell biology of the synapse

The interest of the laboratory is to identify the molecular processes controlling the formation and the function of excitatory and inhibitory synaptic contacts between neurons. Attention is also being paid to the role of glial cells in synaptic development and function under physiological and pathological conditions.

In the past years we have demonstrated that the processes of neuronal maturation and synaptogenesis coincide with: i) the redistribution of neuronal and synaptic components in different neuronal regions (Matteoli et al., J. Cell Biol. 1992; Verderio et al., J. Cell Biol. 1994 ; Verderio et al., PNAS 1995; Coco et al., EJN 1997; Coco et al., J. Neurosci. 1999; Pravettoni et al., Dev. Biol., 2000) and ii) the activation of specific functional mechanisms that regulate synaptic vesicle recycling (Verderio et al., PNAS 1995; Coco et al., J. Neurochem. 1998; Bacci et al., J. Neurosci. 2001, Verderio et al., J. Neurosci.1999; for a review see Matteoli et al., Trends in Cell Biol, 2005).

Current research

From filopodia to synaptic contacts


The process of synaptogenesis is crucial to the development of the nervous system, but the molecular pathways that regulate this process are not fully understood. External cues, such as brain-derived neurotrophic factor (BDNF), trigger synaptogenesis by promoting the formation of axonal filopodia, thin extensions projecting outward from a growing axon. Filopodia are formed by elongation of actin filaments, a process that is regulated by a complex set of actin-binding proteins. We have revealed a novel molecular circuit underlying BDNF-stimulated filopodia formation through the regulated inhibition of actin capping factor activity. We showed that the actin-capping protein Eps8 down-regulates axonal filopodia formation in neurons in the absence of neurotrophic factors. In contrast, in the presence of BDNF, the enzyme MAPK becomes activated and phosphorylates Eps8, leading to inhibition of its actin-capping function and stimulation of filopodia formation, a process with crucial impacts on neuronal development (Menna et al, PLoS Biol 2009). MAPK is also the target of presynaptic AMPA receptors (Schenk et al, EMBO J, 2003). Through MAPK activation, presynaptic AMPA receptors modulate synaptic vesicle traffic, synapsin phosphorylation and induce an increase in evoked synaptic vesicle recycling (Schenk et al., J. Neurosci, 2005). Presynaptic MAPK represents therefore a crucial molecule involved in processes of presynaptic plasticity.

Functional and molecular differences between excitatory and inhibitory terminals

In the last years evidence accumulated that excitatory and inhibitory synapses are characterized by different molecular machineries which control synaptogenesis and synaptic function. SNAP-25 belongs to the SNARE protein family, which is involved in the regulation of priming and fusion of the synaptic vesicles. We have demonstrated that adult rat hippocampal GABAergic synapses, both in culture and in brain, are virtually devoid of SNAP-25 immunoreactivity and are largely resistant to the action of botulinum toxins type A and E, which cleave this protein (Verderio et al, Neuron 2004; Verderio et al, Traffic 2007).


SNAP-25 expression is a developmentally regulated process, and inhibitory synapses lacking SNAP-25 belong to different classes of interneurons (Frassoni et al., Neuroscience 2005). Importantly, SNAP-25 is able to negatively modulate neuronal calcium responsiveness to depolarization (Verderio et al, Neuron 2004) via the inhibition of voltage dependent calcium channels (Pozzi et al, PNAS 2008; Condliffe et al, submitted). Anatomical, electrophysiological and behavioural analysis are currently being carried out in SNAP-25 heterozygous animals, which express half of the protein, to understand the impact of reduced calcium modulation on neuronal physiology (Corradini et al, in preparation).

Role of glial cells in synaptic function

Glial cells are the most abundant cell population in the CNS. They interact with neurons and play a role in controlling synaptogenesis and modulating synaptic networks. In the past years we have demonstrated that astrocytes play an essential role in supporting enhanced synaptic activity via the glutamate/glutamine shuttling between glia and neurons, both in physiological and pathological conditions of the CNS (Bacci et al., EJN 1999; Verderio et al., EJN 1999; Bacci et al, J Neurophysiol, 2002; Armano et al, J Biol Chem, 2002). Importantly astrocytes release neuroactive substances into the extracellular environment. We have identified the existence of different regulated secretory pathways in astrocytes. We have shown that ATP and glutamate are stored in and released from two different populations of vesicles, in particular secretory granules for ATP (Coco et al, JBC 2003) and clear vesicles for glutamate (Crippa et al, J Physiol, 2006; for a review see Montana et al, Glia 2006). The latter vesicles rely on the SNAREs VAMP2 and cellubrevin for their fusion with the plasmamembrane. A third pathway of secretion mediated by the SNARE TI-VAMP has been identified in our lab. Release of neuroactive substances from astrocytes may have important implications for the functioning of the CNS under pathological conditions.


  • Menna E, Disanza A, Cagnoli C, Schenk U, Gelsomino G, Frittoli E, Hertzog M, Offenhauser N, Sawallisch C, Kreienkamp HJ, Gertler FB, Di Fiore PP, Scita G, Matteoli M (2009) Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS Biol. 7:e1000138.
  • Bergami M, Santi S, Formaggio E, Cagnoli C, Verderio C, Blum R, Berninger B, Matteoli M, Canossa M (2008) Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes. J. Cell Biol. 183:213-21.
  • Pozzi D, Condliffe S, Bozzi Y, Chikhladze M, Grumelli C, Proux-Gillardeaux V, Takahashi M, Franceschetti S, Verderio C, Matteoli M (2008) Activity-dependent phosphorylation of Ser187 is required for SNAP-25-negative modulation of neuronal voltage-gated calcium channels. Proc. Natl. Acad. Sci. U.S.A. 105:323-8.
  • Schenk U, Menna E, Kim T, Passafaro M, Chang S, De Camilli P, Matteoli M (2005) A novel pathway for presynaptic mitogen-activated kinase activation via AMPA receptors. J. Neurosci. 25:1654-63.
  • Verderio C, Pozzi D, Pravettoni E, Inverardi F, Schenk U, Coco S, Proux-Gillardeaux V, Galli T, Rossetto O, Frassoni C, Matteoli M (2004) SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization. Neuron 41:599-610.


Telethon Italia (Role of SNAP-25 in the control of Calcium dynamics) 2004-2005

European Community Integrated Project (EUSynapse) 2005-2009

Fondazione CARIPLO (Brain on a chip) 2006-2009

Italian Ministry of University and Research COFIN 2005 (Modulazione del traffico delle vescicole sinaptiche e del rilascio di neurotrasmettitore in neuroni GABAergici e glutamatergici) 2005-2007

Compagnia di San Paolo (Meccanismi molecolari della trasmissione dell'informazione nel SNC: dalla plasticit sinaptica alla patogenesi delle malattie neurologiche) 2008-2010

European Community Large Scale Integrating Project (European Consortium on Synaptic Protein Networks In Neurological and Psychiatric Diseases) 2010-2013

Fondazione CARIPLO (A micro biodevice for the assessment of neuroprotective factors in Parkinson's Disease) 2009-2011


  • G. Scita and P.P. Di Fiore, IFOM, Milan, Italy.
  • Members of EuSynapse and Eurospin Consortia coordinated, respectively, by R. Jahn and N. Brose, Göttingen, Germany
  • Matteo Caleo
  • M. E. Sala, Department of Medical Pharmacology, Università degli Studi di Milano, Milan, Italy.
  • E. Delamarch, IBM, Zürich, Switzerland.


PI photo

Michela Matteoli

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Participating staff