title: Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning.
abstract: ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP-PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ß-catenin-Tyr-654 phosphorylation increased ∼5-fold in the hippocampus of adult PTP1B(-/-) (KO) mice compared to wild type (WT) mice and this was accompanied by a reduction in the amount of ß-catenin associated with N-cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1B(fl/fl)-Emx1-Cre). PTP1B(fl/fl)-Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole), utilized a more efficient strategy (cued), and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of ß-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase.
authors: Instituto de Investigaciones Biotecnológicas, Universidad de San Martín/CONICET, San Martín, Buenos Aires, Argentina.
authors: Federico
authors: F
authors: Fuentes
authors: Derek
authors: D
authors: Zimmer
authors: Marybless
authors: M
authors: Atienza
authors: Jamie
authors: J
authors: Schottenfeld
authors: Ian
authors: I
authors: Penkala
authors: Tracy
authors: T
authors: Bale
authors: Kendra K
authors: KK
authors: Bence
authors: Carlos O
authors: CO
authors: Arregui
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D007858:Learning; D008568:Memory; D051379:Mice; D009473:Neuronal Plasticity; D010766:Phosphorylation; D011247:Pregnancy; D021381:Protein Transport; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism
chemical_list: D015820:Cadherins; D051176:beta Catenin; D014443:Tyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; C516610:Ptpn1 protein, rat