Protein Tyrosine Phosphatase PTP1B Is Involved in Hippocampal Synapse Formation and Learning

Federico Fuentes,Marybless Atienza,Jamie Schottenfeld,Kendra K Bence,Tracy Bale,Ian Penkala,Carlos O Arregui,Derek Zimmer,Anna Dunaevsky

doi:10.1371/journal.pone.0041536

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 (PTP1Bfl/fl–Emx1-Cre). PTP1Bfl/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.

Highlights

The hippocampus has been implicated in memory formation and learning; both of these processes are accompanied by specific modifications in the structure and function of the synapse [1,2,3,4,5]
Dendritic spines develop from dynamic filopodia-like protrusions, which are more abundant in initial phases of synaptogenesis (as seen in 10 days in vitro (DIV) cultures), while mature spines with morphologically distinct heads and necks are the hallmark of later stages (e.g. DIV21 cultures)
Studies in cultured hippocampal neurons showed that impairment of PTP1B function negatively affects axon and dendrite growth, as well as growth cone dynamics [24,54]

Summary

Introduction

The hippocampus has been implicated in memory formation and learning; both of these processes are accompanied by specific modifications in the structure and function of the synapse [1,2,3,4,5]. In vivo conditional deletion of ß-catenin in newborn neurons of postnatal dentate gyrus impairs the formation of branched dendrites [15]. N-cadherin function relies on dynamic interactions with the actin cytoskeleton, in a process mediated by catenins and regulated by tyrosine phosphorylation [16]. Disruption of hippocampal N-cadherin function impaired the consolidation but not the retrieval of contextual fear memory [18]. Another study showed that conditional deletion of ß-catenin in the amygdala impairs consolidation but not acquisition of memory [19]. This work showed that total ß-catenin protein levels in the basolateral amygdala do not change after fear conditioning; phosphorylation of the ß-catenin-Tyr-654 residue and subsequent N-cadherin/ß-catenin interactions are dynamically regulated [19] highlighting the potential importance of Tyr-654 phosphorylation in learning

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