MS imaging and mass spectrometric synaptosome profiling identify PEP-19/pcp4 as a synaptic molecule involved in spatial learning in mice

•MS imaging is a powerful tool to identify key regulators of learning, memory and synaptic plasticity.•PEP-19/pcp4 is differentially expressed between early- and late-phase learning.•PEP-19/pcp4 protein and mRNA levels are upregulated in the late learning phase.•Peptide fragments of PEP-19/pcp4 are present at the synapse.

The Morris water maze (MWM) spatial learning task has been demonstrated to involve a cognitive switch of action control to serve the transition from an early towards a late learning phase. However, the molecular mechanisms governing this switch are largely unknown. We employed MALDI MS imaging (MSI) to screen for changes in expression of small proteins in brain structures implicated in the different learning phases. We compared mice trained for 3 days and 30 days in the MWM, reflecting an early and a late learning phase in relation to the acquisition of a spatial learning task. An ion with m/z of 6724, identified as PEP-19/pcp4 by top-down tandem MS, was detected at higher intensity in the dorsal striatum of the late learning phase group compared with the early learning phase group. In addition, mass spectrometric analysis of synaptosomes confirmed the presence of PEP-19/pcp4 at the synapse. PEP-19/pcp4 has previously been identified as a critical determinant of synaptic plasticity in locomotor learning. Our findings extend PEP-19/pcp4 function to spatial learning in the forebrain and put MSI forward as a valid and unbiased research strategy for the discovery and identification of the molecular machinery involved in learning, memory and synaptic plasticity. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.