Proteolytic Degradation of Hippocampal STEP in LTP and Learning.

Striatal-enriched protein tyrosine phosphatase (STEP) modulates key signaling molecules involved in synaptic plasticity and neuronal function. It is postulated that STEP opposes the development of long-term potentiation (LTP) and that it exerts a restraint on long-term memory (LTM). Here, we examined whether STEP levels are regulated during hippocampal LTP and after training in hippocampal-dependent tasks. We found that after inducing LTP by high frequency stimulation or theta-burst stimulation STEP levels were significantly reduced, with a concomitant increase of STEP levels, a product of calpain cleavage. Importantly, inhibition of STEP with TC-2153 improved LTP in hippocampal slices. Moreover, we observed that after training in the passive avoidance and the T-maze spontaneous alternation task, hippocampal STEP levels were significantly reduced, but STEP levels were unchanged. Yet, hippocampal BDNF content and TrkB levels were increased in trained mice, and it is known that BDNF promotes STEP degradation through the proteasome. Accordingly, hippocampal pTrkB, pPLCγ, and protein ubiquitination levels were increased in T-SAT trained mice. Remarkably, injection of the TrkB antagonist ANA-12 (2 mg/Kg, but not 0.5 mg/Kg) elicited LTM deficits and promoted STEP accumulation in the hippocampus. Also, STEP knockout mice outperformed wild-type animals in an age- and test-dependent manner. Summarizing, STEP undergoes proteolytic degradation in conditions leading to synaptic strengthening and memory formation, thus highlighting its role as a molecular constrain, which is removed to enable the activation of pathways important for plasticity processes.