Altered Intracellular Calcium Homeostasis Underlying Enhanced Glutamatergic Transmission in Striatal-Enriched Tyrosine Phosphatase (STEP) Knockout Mice
- 225 Downloads
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.
KeywordsStriatal-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.
- 8.Oyama T, Goto S, Nishi T, Sato K, Yamada K, Yoshikawa M, Ushio Y (1995) Immunocytochemical localization of the striatal enriched protein tyrosine phosphatase in the rat striatum: a light and electron microscopic study with a complementary DNA-generated polyclonal antibody. Neuroscience 69:869–880CrossRefPubMedGoogle Scholar
- 16.Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P et al (2010) Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model. Proc Natl Acad Sci U S A 107:19014–19019CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Wu Y, Whiteus C, Xu CS, Hayworth KJ, Weinberg RJ, Hess HF, De Camilli P (2017) Contacts between the endoplasmic reticulum and other membranes in neurons. Proc Natl Acad Sci U S A 114:E4859-E4867Google Scholar