Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice

Department of Anatomy, University of Vermont College of Medicine, Burlington, 05405, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 11/2006; 99(2):499-513. DOI: 10.1111/j.1471-4159.2006.04112.x
Source: PubMed


Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are closely related neurotrophic peptides of the secretin/glucagon family. The two peptides are derived from a common ancestral gene and share many functional attributes in neuronal development/regeneration which occur not only from overlapping receptor subtype signaling but also through common mechanisms regulating their expression. Although PACAP or VIP null mice have been generated for study, it is unclear whether the expression of the complementary peptide or their receptor systems are altered in a compensatory manner during nervous system development. By radioimmunoassay and quantitative PCR measurements, we first show that PACAP and VIP have very different temporal patterns of expression in developing postnatal mouse brain. In wild-type animals, PACAP transcript and peptide levels increased rapidly 2- and 5-fold, respectively, within 1 week of age. These levels at 1 week of age were maintained through adulthood. VIP transcript and peptide levels, by contrast, increased 25- and 50-fold, respectively, over a later time course. In parallel studies of development, there were no apparent compensatory increases in brain VIP expression in the PACAP knockout animals, PACAP expression in the VIP-deficient animals, or receptor mRNA levels in either genotype. To the contrary, there was evidence for developmental delays in the expression of peptide and receptor transcripts in the knockout animals. A series of behavioral and neurological tests demonstrated differences between the knockout genotypes, revealing some functional distinctions between the two genes. These results suggest that the PACAP and VIP have evolved to possess distinct biological activities and intimate that the respective knockout phenotypes represent deficits unmitigated by the actions of the complementary related peptide.


Available from: Vincent Lelièvre, Sep 15, 2014
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    • "Pituitary adenylate cyclase-activating peptide (PACAP) and its cognate G protein-coupled PAC1 receptor are highly expressed in areas that modulate responses to stress, including the BNST (Arimura et al. 1991; Nomura et al. 1996; Shioda et al. 1997; for review, see Vaudry et al. 2009). Consistent with a role in stress responding, PACAP or PAC1 receptor null mice have altered corticosterone circadian rhythm, diminished HPA activation after prolonged stressor exposure (Hashimoto et al. 2009; Stroth and Eiden 2010; Hattori et al. 2012), reduced anxiety-like behavior and fear (Hashimoto et al. 2001; Otto et al. 2001a, b; Girard et al. 2006), and impaired contextual fear conditioning (Otto et al. 2001a). Intra-BNST PACAP infusion increases both anxiety-like behavior (Hammack et al. 2009) and anorexia in rats (Kocho- Schellenberg et al. 2014). "
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    ABSTRACT: Single-nucleotide polymorphisms (SNPs) in the genes for pituitary adenylyl cyclase-activating peptide (PACAP) and the PAC1 receptor have been associated with stress-related psychiatric disorders. Although, from recent work, we have argued that stress-induced PACAP expression in the bed nucleus of the stria terminalis (BNST) may mediate stress-related psychopathology, it is unclear whether stress-induced increases in BNST PACAP expression require acute or repeated stressor exposure and whether increased BNST PACAP expression is related to stress-induced increases in circulating glucocorticoids. In the current work, we have used real-time quantitative polymerase chain reaction (qPCR) to assess transcript expression in brain punches from rats after stressor exposure paradigms or corticosterone injection. BNST PACAP and PAC1 receptor transcript expression was increased only after 7 days of repeated stressor exposure; no changes in transcript levels were observed 2 or 24 hours after a single-restraint session. Moreover, repeated corticosterone treatment for 7 days was not sufficient to reliably increase BNST PACAP transcript levels, suggesting that stress-induced elevations in corticosterone may not be the primary drivers of BNST PACAP expression. These results may help clarify the mechanisms and temporal processes that underlie BNST PACAP induction for intervention in stress-related anxiety disorders.
    Journal of Molecular Neuroscience 03/2014; 54(3). DOI:10.1007/s12031-014-0269-8 · 2.34 Impact Factor
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    • "Mouse with VIP receptor antagonist prenatal treatment + Deficit in sociability and no preference for social novelty in males, ↑ sociability and the same level in preference for social novelty in females Hill et al. (2007) Hill et al. (2007) VIP deficient mouse + ↓ maternal affiliation, ↓ play behaviour, and deficits in social approach in male offspring Girard et al. (2006) Lim et al. (2008) and Stack et al. (2008) V1aR KO mouse + ↓ in anxiety-like behaviour along with impairment in social recognition and interactions Bielsky et al. (2004) Bielsky et al. (2004) and Egashira et al. (2007) V1bR KO mouse + ↓ social recognition and aggression, modified social preference, and ↓ ultrasonic vocalization at lower frequencies Wersinger et al. (2002) Wersinger et al. (2002) (2004) and Scattoni et al. (2008b) Abbreviations: ↓, decreased; ↑, increased; ACC, anterior cingulate cortex; AMY, amygdala; Ar, aromatase; AVP, vasopressin; CER, cerebellum; CC, corpus callosum; En 2, engrailed 2; GABA, gamma-aminobutyric acid; GABrb3, beta-3 subunit of Gamma-aminobutyric acid receptor; GLU, glutamate; GlutD1, glutamate delta 1 receptor; HIP, hippocampus; KO, knock-out; OFC, orbitofrontal cortex; OT, oxytocin; OTR, oxytocin receptor; PFC, prefrontal cortex; SER, serotonin; Shank3, SH3 and multiple ankyrin repeat domains 3; Slc6a4, solute carrier family 6 (neurotransmitter transporter, serotonin), member 4; STR, striatum; V1aR, arginine vasopressin receptor 1A; V1bR, arginine vasopressin receptor 1B; VIP, vasoactive intestinal peptide; VPA, valproic acid. Table 2 The genetically altered animal models that represent examples of models of autism susceptibility genes and show behavioural phenotypes reflecting social deficit. "
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    ABSTRACT: Research on autism has been gaining more and more attention. However, its aetiology is not entirely known and several factors are thought to contribute to the development of this neurodevelopmental disorder. These potential contributing factors range from genetic heritability to environmental effects. A significant number of reviews have already been published on different aspects of autism research as well as focusing on using animal models to help expand current knowledge around its aetiology. However, the diverse range of symptoms and possible causes of autism have resulted in as equally wide variety of animal models of autism. In this update article we focus only on the animal models with neurobehavioural characteristics of social deficit related to autism and present an overview of the animal models with alterations in brain regions, neurotransmitters, or hormones that are involved in a decrease in sociability.
    Neuroscience Research 11/2012; 74(3-4). DOI:10.1016/j.neures.2012.10.004 · 1.94 Impact Factor
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    • "Other compensatory mechanisms operating in PACAP KO mice might involve VIP and/or any one of the receptors that bind these peptides: VPAC1, VPAC2, or PAC1. However, in a previous study, no observable increases in the expression of VIP or any of the VIP or PACAP receptors were observed in the developing brain of postnatal PACAP KO mice compared to WT animals (Girard et al., 2006). Thus, increased expression of VIP and/or PACAP or VIP receptors appears not to be a general compensatory mechanism for loss of PACAP. "
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    ABSTRACT: Pituitary adenylyl cyclase-activating peptide (PACAP; ADCYAP1) is a neuropeptide that regulates a wide array of functions within the brain and periphery. We and others have previously demonstrated that PACAP and its high-affinity receptor PAC1 are expressed in the embryonic mouse neural tube, suggesting that PACAP plays a role in early brain development. Moreover, we previously showed that PACAP antagonizes the mitotic action of Sonic hedgehog (Shh) in postnatal cerebellar granule precursors. In the present study, we demonstrate that PACAP completely blocked Shh-dependent motor neuron generation from embryonic stem cell cultures and reduced mRNA levels of the Shh target gene Gli-1 and several ventral spinal cord patterning genes. In vivo examination of motor neuron and other patterning markers in embryonic day 12.5 spinal cords of wild-type and PACAP-deficient mice by immunofluorescence, on the other hand, revealed no obvious alterations in expressions of Islet1/2, MNR2, Lim1/2, Nkx2.2, or Shh, although the Pax6-positive area was slightly expanded in PACAP-deficient spinal cord. Caspase-3 staining revealed low, and similar, numbers of cells undergoing apoptosis in embryonic wild-type vs. PACAP-deficient spinal cords, whereas a slight but significant increase in number of mitotic cells was observed in PACAP-deficient mice. Thus, although PACAP has a strong capacity to counteract Shh signaling and motor neuron production in vitro, corresponding patterning defects associated with PACAP loss may be obscured by compensatory mechanisms.
    Journal of Neuroscience Research 09/2011; 89(9):1363-74. DOI:10.1002/jnr.22675 · 2.59 Impact Factor
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