Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Involved in Adult Mouse Hippocampal Neurogenesis After Stroke

Abstract

In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.

Review on PACAP-Induced Transcriptomic and Proteomic Changes in Neuronal Development and Repair

“…PACAP occurs at highest concentrations in the nervous system, where it functions as a neuromodulatory and neurotransmitter peptide. In the nervous system, PACAP acts, amongst others, on hypothalamic hormone release and hypothalamo-hypophyseal hormonal regulatory pathways [ 3 , 4 ], on central thermoregulatory and feeding routes [ 5 , 6 , 7 , 8 ], on neurogenesis [ 9 ] and on cognitive performance [ 10 , 11 , 12 ]. Of special importance is the action of PACAP on neuronal proliferation, differentiation and migration, whereby the peptide has significant effects in the development of the nervous system [ 13 , 14 ].…”

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors

“…2A, a vs a). PACAP contributes to neuronal stem cell proliferation [24], energy balance [25], and differentiation [26,27]. Cell growth of PRNCs was not affected by PACAP-27/38 (Fig.…”

Protective effects of PACAP in ischemia

“…It was also suggested that these protective effects could be mediated in part by IL-6 [ 40 ]. Endogenous PACAP also promotes hippocampal neurogenesis after stroke, as proliferation of neuronal stem cells in the subgranular zone of the hippocampus was found to be increased in wild type mice, but not in PACAP heterozygous animals [ 72 ].…”