Prolyl Endopeptidase-Deficient Mice Have Reduced Synaptic Spine Density in the CA1 Region of the Hippocampus, Impaired LTP, and Spatial Learning and Memory

Abstract

Prolyl endopeptidase (PREP) is a phylogenetically conserved serine protease and, in humans and rodents, is highly expressed in the brain. Several neuropeptides associated with learning and memory and neurodegenerative disorders have been proposed to be the substrates for PREP, suggesting a possible role for PREP in these processes. However, its physiological function remains elusive. Combining genetic, anatomical, electrophysiological, and behavioral approaches, we show that PREP genetrap mice have decreased synaptic spine density in the CA1 region of the hippocampus, reduced hippocampal long-term potentiation, impaired hippocampalmediated learning and memory, and reduced growth-associated protein-43 levels when compared with wild-type controls. These observations reveal a role for PREP in mediating hippocampal plasticity and spatial memory formation, with implications for its pharmacological manipulation in diseases related to cognitive impairment.

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

“…In the central nervous system, Prep mRNA was found in the hypothalamus (Fig. 1A), hippocampus, and cortex (5,6). Within the hypothalamus, higher expression of Prep mRNA was detected in the ventromedial nucleus (VMH) (Fig.…”

“…Prep gt/gt male mice were perfused with 4% paraformaldehyde. Brains were sectioned (50 μm), washed in PBS, and incubated overnight at 37°C in the staining solution containing 25 mM K 3 Fe(CN) 6 , 25 mM K 4 Fe (CN) 6 3H2O, 2 mM MgCl 2 in PBS, and 1 mg/mL of X-Gal.…”

“…In humans and rodents it is highly expressed in the brain (2), including the cortex, striatum, hypothalamus, hippocampus, and amygdala (3)(4)(5)(6). The physiological role of PREP remains elusive (7).…”

Prolyl Endopeptidase (PREP) is Associated With Male Reproductive Functions and Gamete Physiology in Mice

“…In fact, it was suggested that PREP may be released from the cells (Ahmed et al, ), even though it lacks a secretion signal and it does not contain a transmembrane region, or a lipid anchor sequence (Venäläinen et al, ). PREP has been implicated in several biological processes, including cognitive disorders (Rossner et al, ; Hannula et al, ), celiac disease (Siegel et al, ; Comino et al, ), cell death (Bär et al, ; Matsuda et al, ), learning and memory (Irazusta et al, ; D'Agostino et al, ), cell proliferation and differentiation (Matsubara et al, ; Suzuki et al, ), and glucose metabolism (Kim et al, ). However, its physiological role remains to be elucidated.…”

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

“…In the healthy brain, PREP is present mostly in neurons: in the cytoplasm, around the nucleus along the microtubules, and at the tips of the neurites. 23,24 PREP overexpression has been shown to reduce the levels of polysialylated neural cell adhesion molecule (PSA-NCAM), whereas in PREP-negative mice, PSA-NCAM level was increased. 17 PREP expression is also upregulated in glial cells after activation with lipopolysaccharide (LPS) 13 and is found to be neurotoxic to co-cultured neuronal cells, an effect that was reversed by PREP inhibitors.…”