Animals lacking endothelin‐converting enzyme‐2 are deficient in learning and memory

Abstract

Endothelin‐converting enzyme (ECE)‐2 is a metalloprotease that possesses many properties consistent with it being a neuropeptide‐processing enzyme. This protease is found primarily in neural tissues, with high levels of expression in midbrain, cerebellum, hypothalamus, frontal cortex and spinal cord and moderate levels in hippocampus and striatum. To evaluate its role in neural function, mice have been generated lacking this enzyme. Physical appearance, autonomic reflexes, motor co‐ordination, balance, locomotor activity and spontaneous emotional responses appear normal in these knockout (KO) mice. However, these mutants display deficits in learning and memory as evidenced by marked impairment in the Morris water maze. Knockout mice are also deficient in object recognition memory where they show delays in discerning changes in object location and in recognizing the introduction of a novel object. In this study, perseveration appears to interfere with learning and memory. Finally, mutants are impaired in social transmission of food preference where they show poor short‐term memory and perturbations in long‐term memory; the latter can be ameliorated by reminder cues. As ECE‐2 has been implicated in Alzheimer’s disease, the deficits in learning and memory in the KO mice may provide unique insights into processes that may contribute to this disease and possible other disorders of cognition.

Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

“…Processing of opioid peptides by ECE2 is likely to be of physiological significance as suggested by its distribution, which overlaps with the distribution of opioid peptide precursors such as proenkephalin (11,59), and its selective substrate specificity in processing opioid peptides (13). A previous study that analyzed the substrate specificity of ECE2 in vitro revealed that among the opioid peptides tested, Dyn B-13, BAM22, BAM18, and peptide E were selectively processed by ECE2 (13), and it is interesting to note that BAM22 and BAM18 were processed to yield BAM12 (13).…”

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

“…The procedures for the neurophysiological screen, STFP, NORM, Morris water maze, fear conditioning, and FPS have been described previously (26,27). In pharmacology studies, mice were injected (i.p.)…”

“…WT and PC7 KO mice were indistinguishable on tests of gross sensory and motor performance (Table S3). Episodic memory, recollection of past events or experiences, was examined with the social transmission of food preference (STFP) and the novel object recognition memory (NORM) tests (26). To monitor STFP, a demonstrator mouse that ate a flavored diet was returned to its home cage to interact with its cage-mates.…”

Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice

“…The ET-1/ECE-1/ET A pathway is essential for the development of pharyngeal arch-derived, craniofacial, and cardiac tissues (2,3), whereas the ET-3/ECE-1/ET B pathway is essential for the development of the enteric nervous system and skin melanocytes (4,5). Although Ece-2-null mice revealed no marked abnormalities (6), Ece-1/Ece-2 double mutants exhibited more severe cardiac abnormalities, including endocardial cushion defects (7). These molecular genetic studies point to the highly local action of ETs.…”