Cell-type specific knockout of peptidylglycine α-amidating monooxygenase reveals specific behavioral roles in excitatory forebrain neurons and cardiomyocytes.

Neuropeptides and peptide hormones play a crucial role in integrating the many factors that affect physiologic and cognitive processes. The potency of many of these peptides requires an amidated amino acid at the C-terminus; a single enzyme, peptidylglycine α-amidating monooxygenase (PAM), catalyzes this modification. Anxiety-like behavior is known to be altered in mice with a single functional Pam allele (Pam ) and in mice unable to express Pam in excitatory forebrain neurons (Pam ) or in cardiomyocytes (Pam ). Examination of PAM-positive and glutamic acid decarboxylase 67 (GAD)-positive cells in the amygdala of Pam mice demonstrated the absence of PAM in pyramidal neurons and its continued presence in GAD-positive interneurons, suggestive of altered excitatory/inhibitory balance. Additional behavioral tests were used to search for functional alterations in these cell-type specific knockout mice. Pam mice exhibited a less focused search pattern for the Barnes Maze escape hole than control or Pam mice. While wildtype mice favor interacting with novel objects as opposed to familiar objects, both Pam and Pam mice exhibited significantly less interest in the novel object. Since PAM levels in the central nervous system of Pam mice are unaltered, the behavioral effect observed in these mice may reflect their inability to produce atrial granules and the resulting reduction in serum levels of atrial natriuretic peptide. In the sociability test, male mice of all three genotypes spent more time with same-sex stranger mice; while control females showed no preference for stranger mice, female Pam mice showed preference for same-sex stranger mice in all trials.