title: The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity.
abstract: STriatal-Enriched protein tyrosine Phosphatase (STEP; PTPN5) is expressed in brain regions displaying adult neuroplasticity. STEP modulates neurotransmission by dephosphorylating regulatory tyrosine residues on its substrates. In this way, STEP inactivates extracellular-signal-regulated kinase 1/2 (ERK1/2), limiting the duration and spatial distribution of ERK signaling. Two additional substrates, the tyrosine kinase Fyn and the NR2B subunit of the N-methyl-d-aspartic acid receptor, link STEP to glutamate receptor internalization in the synapse. Thus, STEP may act through parallel pathways to oppose the development of experience-dependent synaptic plasticity. We examined the hypothesis that the absence of STEP facilitates amygdala-dependent behavioral and synaptic plasticity (i.e., fear conditioning and long-term potentiation) using STEP-deficient mice (STEP KO). These mice show no detectable expression of STEP in the brain along with increases in Tyr phosphorylation of STEP substrates. Here we demonstrate that STEP KO mice also display augmented fear conditioning as measured by an enhancement in conditioned suppression of instrumental response when a fear-associated conditioned stimulus was presented. Deletion of STEP also increases long-term potentiation and ERK phosphorylation in the lateral amygdala. The current experiments demonstrate that deletion of STEP can enhance experience-induced neuroplasticity and memory formation and identifies STEP as a target for pharmacological treatment aimed at improving the formation of long-term memories.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA. peter.olausson@yale.edu
authors.forename: P
authors.initials: P
authors.lastname: Olausson
authors.forename: D V
authors.initials: DV
authors.lastname: Venkitaramani
authors.forename: T D
authors.initials: TD
authors.lastname: Moran
authors.forename: M W
authors.initials: MW
authors.lastname: Salter
authors.forename: J R
authors.initials: JR
authors.lastname: Taylor
authors.forename: P J
authors.initials: PJ
authors.lastname: Lombroso
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D003216:Conditioning, Operant / Q000502:physiology*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005239:Fear / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology
chemical_list: C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor