Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities including modulation of synaptic plasticity and memory, hippocampal neurogenesis, and neuroprotection, most of which are shared with brain-derived neurotrophic factor (BDNF). Therefore, the aim of this study was to compare morphological effects of PACAP and BDNF on primary cultured hippocampal neurons. At days in vitro (DIV) 3, PACAP increased neurite length and number to similar levels by BDNF, but vasoactive intestinal polypeptide showed much lower effects. In addition, PACAP increased axon, but not dendrite, length, and soma size at DIV 3 similarly to BDNF. The PACAP antagonist PACAP6–38 completely blocked the PACAP-induced increase in axon, but not dendrite, length. Interestingly, the BDNF-induced increase in axon length was also inhibited by PACAP6–38, suggesting a mechanism involving PACAP signaling. K252a, a TrkB receptor inhibitor, inhibited axon outgrowth induced by PACAP and BDNF without affecting dendrite length. These results indicate that in primary cultured hippocampal neurons, PACAP shows morphological actions via its cognate receptor PAC1, stimulating neurite length and number, and soma size to a comparable extent as BDNF, and that the increase in total neurite length is ascribed to axon outgrowth.
Highlights
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide that acts as a neurotransmitter, neuromodulator, and neurotrophic factor via three heptahelical G protein-coupled receptors: a PACAP-preferring (PAC1) receptor and two vasoactive intestinal polypeptide (VIP)-shared (VPAC1 and VPAC2) receptors [1]
A recent study conducted on primary cultured hippocampal neurons found that exogenous PACAP dose-dependently increases the ratio of neurite length to soma size during the first 2
PACAP induced a transient increase in soma size at days in vitro (DIV) 1 through 3, while brain-derived neurotrophic factor (BDNF) showed a similar effect at DIV 3 only (Fig. 2D)
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide that acts as a neurotransmitter, neuromodulator, and neurotrophic factor via three heptahelical G protein-coupled receptors: a PACAP-preferring (PAC1) receptor and two vasoactive intestinal polypeptide (VIP)-shared (VPAC1 and VPAC2) receptors [1]. It has been shown that chronic stress dramatically increases PACAP and PAC1 receptor, and BDNF and TrkB receptor mRNA expression in the dorsolateral bed nucleus of the stria terminalis (BNST) [6], a nucleus known to mediate chronic stress responses associated with enhanced BNST dendritic branching and volume [15] This suggests that trophic functions of PACAP and its coordinate effects with chronic stress-induced BNST BDNF and TrkB transcript expression, may underlie maladaptive BNST remodeling and plasticity associated with stress induced behavioral changes [6,16]. The increase of BDNF levels in the hippocampus induced by enriched rearing is not affected in PACAP-deficient mice (our unpublished observation) These findings suggest that PACAP signaling is critically involved in neuroplastic changes responsible for environmental stimuli that are at least partly mediated via cytoarchitectural changes, either in cooperation with, or independently of, BDNF signaling
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