Molecular Neurobiology

, Volume 55, Issue 10, pp 8084–8102 | Cite as

Altered Intracellular Calcium Homeostasis Underlying Enhanced Glutamatergic Transmission in Striatal-Enriched Tyrosine Phosphatase (STEP) Knockout Mice

  • Federica Bosco
  • Pierluigi Valente
  • Marco Milanese
  • Alessandra Piccini
  • Mirko Messa
  • Giambattista Bonanno
  • Paul Lombroso
  • Pietro Baldelli
  • Fabio Benfenati
  • Silvia Giovedì


The striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase involved in synaptic transmission. The current hypothesis on STEP function holds that it opposes synaptic strengthening by dephosphorylating and inactivating key neuronal proteins involved in synaptic plasticity and intracellular signaling, such as the MAP kinases ERK1/2 and p38, as well as the tyrosine kinase Fyn. Although STEP has a predominant role at the post-synaptic level, it is also expressed in nerve terminals. To better investigate its physiological role at the presynaptic level, we functionally investigated brain synaptosomes and autaptic hippocampal neurons from STEP knockout (KO) mice. Synaptosomes purified from mutant mice were characterized by an increased basal and evoked glutamate release compared with wild-type animals. Under resting conditions, STEP KO synaptosomes displayed increased cytosolic Ca2+ levels accompanied by an enhanced basal activity of Ca2+/calmodulin-dependent protein kinase type II (CaMKII) and hyperphosphorylation of synapsin I at CaMKII sites. Moreover, STEP KO hippocampal neurons exhibit an increase of excitatory synaptic strength attributable to an increased size of the readily releasable pool of synaptic vesicles. These results provide new evidence that STEP plays an important role at nerve terminals in the regulation of Ca2+ homeostasis and neurotransmitter release.


Striatal-enriched tyrosine phosphatase Synaptosomes Glutamate release Ca2+ homeostasis Synapsin I CaMKII Synaptic transmission 



We thank Dr. Paul Greengard (The Rockefeller University, New York, NY) for providing us with the phosphorylation-state-specific antibodies of synapsin I, Dr. Cesare Usai (National Research Council, Genova, Italy) for the use of microspectrofluorometer and helpful discussions, and Dr. Silvia Casagrande (University of Genova, Italy) for assistance in the preparation of primary cultures. This study was supported by research grants from the Italian Ministry of University and Research (PRIN 2010/11 to FB and FIRB 2010 “Futuro in Ricerca” to SG). The support of Telethon-Italy (Grant GGP13033 to FB) is also acknowledged.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Federica Bosco
    • 1
  • Pierluigi Valente
    • 1
  • Marco Milanese
    • 2
  • Alessandra Piccini
    • 1
  • Mirko Messa
    • 1
    • 3
    • 4
  • Giambattista Bonanno
    • 2
  • Paul Lombroso
    • 5
  • Pietro Baldelli
    • 1
    • 3
  • Fabio Benfenati
    • 1
    • 3
  • Silvia Giovedì
    • 1
  1. 1.Department of Experimental MedicineUniversity of GenovaGenoaItaly
  2. 2.Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical ResearchUniversity of GenovaGenoaItaly
  3. 3.Center for Synaptic Neuroscience and TechnologiesIstituto Italiano di TecnologiaGenoaItaly
  4. 4.Department of Cell BiologyYale University School of MedicineNew HavenUSA
  5. 5.Child Study CenterYale University School of MedicineNew HavenUSA

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