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

• Published in: Molecular neurobiology Vol. 55; no. 10; pp. 8084 - 8102
• Main Authors: Bosco, Federica, Valente, Pierluigi, Milanese, Marco, Piccini, Alessandra, Messa, Mirko, Bonanno, Giambattista, Lombroso, Paul, Baldelli, Pietro, Benfenati, Fabio, Giovedì, Silvia
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2018; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Brain; Ca2+/calmodulin-dependent protein kinase II; Calcineurin - metabolism; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium homeostasis; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Cell Biology; Cytosol - metabolism; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Fyn protein; Glutamatergic transmission; Glutamic Acid - metabolism; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Homeostasis; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Intracellular; Intracellular signalling; Intracellular Space - metabolism; Kinases; Mice; Mice, Knockout; Models, Biological; Mutation - genetics; Neostriatum; Neostriatum - metabolism; Nerve endings; Neurobiology; Neurology; Neurosciences; Neurotransmitter release; Phosphatase; Phosphorylation; Presynaptic Terminals - metabolism; Protein Tyrosine Phosphatases, Non-Receptor - deficiency; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Protein-tyrosine kinase; Protein-tyrosine-phosphatase; Proteins; Rodents; Synapses - metabolism; Synapsin I; Synapsins - metabolism; Synaptic plasticity; Synaptic strength; Synaptic Transmission; Synaptic vesicles; Synaptosomes; Synaptosomes - metabolism; Synapsin I; homeostasis; Glutamate release; CaMKII; Synaptic transmission; Synaptosomes; Striatal-enriched tyrosine phosphatase; Ca; Ca2+ homeostasis
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-0980-5

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 Ca 2+ levels accompanied by an enhanced basal activity of Ca 2+ /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 Ca 2+ homeostasis and neurotransmitter release.