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Hippocampus Development is Deficient in Mice with PACAP Signaling System Alterations

by
Liana Ioana Tascau
M.S., University of Bucharest - 2004



Thesis Advisor: Emanuel DiCicco-Bloom, M.D.
Graduate Program in Neuroscience

CABM, Room 010
Piscataway

Thursday, July 21, 2011
9:30 a.m.


Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) and its main receptor, PAC1R, are abundantly expressed in the mouse hippocampus during all stages of development. Although adult mice with deficient PACAP signaling exhibit impaired hippocampal dependent learning and memory, no morphological abnormalities of the hippocampus have been described in these mice. However, given PACAPís roles in regulating neural precursor cell proliferation, neuronal survival and maturation, we now define the developmental functions of PACAP signaling in the hippocampus using PACAP and PAC1R knock out (KO) mice as models.
At P1, mice lacking PACAP or PAC1R have normally developed hippocampi. At P21, however, the hippocampus is smaller in both mutants, with 6-9% reduction in hippocampus weight and 14-22% reduction in the volumes of the dentate gyrus (DG) and Cornu Ammon 1-3 (CA1-3). The weight and volume deficits are associated with 12-15% lower granule and pyramidal cell numbers. These developmental deficits persist into adulthood, when both KO mice have 8-12% less granule and pyramidal neurons. We hypothesized that in PACAP deficient mice, the hippocampus developmental deficits are due to postnatal decrease in DG proliferation and/or increased hippocampal cell death. To examine proliferation, we analyzed BrdU immunostaining after BrdU treatment, employed to label progenitors in S-phase of the cell cycle. We analyzed cell death by using activated caspase 3 immunostaining (Casp3) as a marker for apoptotic cell death. In both mutants, the absence of PACAP signaling at P7 is associated a 22-33% reduction in BrdU(+) cells. With regard to apoptosis, in PAC1R KO mice, Casp3 labeling was normal before birth, at E18.5, but was increased by 55% increase in CA1-3 and 2-fold increase in DG at P7, and remained elevated in the adult. Similar increases in apoptosis were found in the PACAP KO. In conclusion, in the absence of PACAP signaling, there are decreases in proliferation and increases in neuronal cell death which contribute to overall reductions in the two main neuronal hippocampal populations, the granule cells of DG and CA1-3 pyramidal neurons.


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