Hippocampal changes in mice lacking an active prohormone convertase 2.

ABSTRACT

Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2-null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2-null state may affect the function of the hippocampus. In this study, adult PC2-null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2-null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field-excitatory postsynaptic potentials (EPSP), long-term potentiation (LTP), and paired-pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2-null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2-null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2-null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2-null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2-null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2-null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.