Keywords

Introduction

Pituitary adenylate cyclase-activating polypeptide (PACAP) [1] is widely distributed in the central nervous system and can act as a neurohormone, neurotransmitter, or trophic factor [2]. PACAP exerts multiple activities via three subtypes of G protein-coupled receptors, one PACAP-specific (PAC1) receptor and two receptors that are shared with vasoactive intestinal peptide (VIP) (VPAC1 and VPAC2). Accumulating evidence implicates PACAP signaling as an important regulator of psychiatric functions and suggests that genetic variation of PACAP and VPAC2 may be a risk factor for psychiatric disorders including schizophrenia and stress-related disorders. Such evidence has come from studies in both animal models and human clinical research, as well as through their bidirectional translation.

In this chapter, we briefly review our current knowledge in terms of the psychiatric implication of PACAP. Although we do not cover all contributions to the field, for detailed information, excellent reviews are available in this book and others [3–9].

Animal Studies

PACAP-deficient mice show behavioral and neurophysiological abnormalities that can potentially be correlated with psychiatric disorders and their related endophenotypes (Fig. 44.1). PACAP-deficient mice show hyperlocomotion and abnormally high-frequent jumping, increased novelty-seeking behavior, decreased anxiety-like behavior, and impaired social interaction [10–14]. The mutants have been shown to exhibit exaggerated depression-like behavior in the forced-swimming test [14, 15] and impaired prepulse inhibition of acoustic startle response [16]. However, these mice also demonstrated normal levels of depression-like behavior [17] and prepulse inhibition [13]. These discrepancies may reflect differences in behavioral protocols (behavioral tests each conducted in naïve mice vs. behavioral test batteries) and/or mouse genetic background. In addition, PACAP mutant mice show deficits in working memory [13, 18] and long-term potentiation in the dentate gyrus in vivo [19].

Fig. 44.1
figure 1

Behavioral phenotypes in PACAP- and PAC1 receptor-mutant mice, treatments ameliorative against the behavioral phenotypes of PACAP-knockout mice, and potential mechanisms of PACAP-dependent behavioral and neurophysiological regulation. LTP long-term potentiation, 5-HT serotonin, mGluR metabotropic glutamate receptor, icv intracerebroventricular

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Mutant mice with complete (ubiquitous) or forebrain-specific deletion of the PACAP receptor PAC1 show a deficit in contextual fear conditioning, a hippocampal-dependent associative learning task, and impaired long-term potentiation at mossy fiber-CA3 synapses [20]. Hyperlocomotion and markedly reduced anxiety-like behavior have also been described in PAC1 receptor-deficient mice, but not in forebrain-specific PAC1 receptor mutant mice [21]. Furthermore, PAC1 receptor-deficient mice display markedly abnormal social behaviors [22].

The diversified behavioral and neurophysiological abnormalities in PACAP and PAC1 receptor mutant mice correlate with psychiatric disorders and their related endophenotypes and can be grouped into psychotic agitation (hyperlocomotion and abnormally high-frequent jumping), emotional (affective) components (anxiety-like behavior, depression-like behavior, and impaired social interaction), and cognitive deficits (memory deficits and impaired prepulse inhibition), although impaired social interaction may also be grouped as cognitive deficits.

Interestingly, some of the abnormalities in PACAP-deficient mice are clearly ameliorated by antipsychotic drugs, particularly with risperidone, an atypical antipsychotic drug and serotonin dopamine antagonist [10, 15, 16]. In addition, psychomotor and memory deficits in PACAP-deficient mice are ameliorated by MGS0028, a selective agonist of the metabotropic glutamate 2/3 receptor [23], and by SB-269970, a selective antagonist of the serotonin 7 receptor [18] (Fig. 44.1). Both the metabotropic glutamate 2/3 receptor and serotonin 7 receptor attract much attention owing to their therapeutic potential for psychiatric diseases. Thus, these results suggest that PACAP-deficient mice can be used as an animal model to develop new drugs for reversing neurobehavioral deficits.

Genetic Studies in Humans

Table 44.1 shows some, but not all, genetic variations of the genes for PACAP and the PACAP receptors, PAC1 and VPAC2, which have been suggested to be associated with an increased risk of psychiatric disorders and their postulated endophenotypes.

Table 44.1 Genetic variations of the PACAP and PACAP receptor genes associated with an increased risk of psychiatric disorders and their possible endophenotypesa
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The single nucleotide polymorphisms (SNPs) in the PACAP gene (rs1893154 and rs2856966) and PAC1 receptor gene (rs2302475) were shown to be associated with schizophrenia [24]. Homozygous carriers of the G allele of the SNP rs1893154 of the PACAP gene had smaller bilateral hippocampal volumes and lower visual associative memory performance compared with A-carriers [24]. rs1893154 was also associated with major depressive disorder [25] (Table 44.1).

A copy number variation (CNV) of the PACAP gene owing to a partial trisomy 18p and monosomy 20p has been identified in two related patients. These patients have three copies of the PACAP gene and elevated PACAP concentrations in plasma and suffer from mental retardation, psychotic behavior, and hyperactive behavior. In addition to these neurological problems, the patients also have gastrointestinal and endocrinological problems, including a bleeding tendency with mild thrombocytopenia [26] (Table 44.1).

A female-specific association of the PACAP-PAC1 receptor pathway with post-traumatic stress disorder (PTSD) has been observed [27]. The SNP rs2267735 located in a putative estrogen response element of the PAC1 receptor gene is associated with PTSD diagnosis and symptoms. Recent functional magnetic resonance imaging studies showed that rs2267735 was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between these brain regions in a traumatized cohort of women [28], as well as with decreased hippocampal activity during contextual fear conditioning in healthy females [29]. rs2267735 has also been shown to be associated with dark-enhanced startle in children [30] (Table 44.1). In addition to genetic variants, blood levels of PACAP have been shown to associate with PTSD in females, proposing that PACAP levels and PAC1 receptor gene SNPs may serve as biomarkers of PTSD [27].

The VPAC2 receptor, also known as VIPR2, is a common G-protein coupled receptor for PACAP and VIP [2]. Recently, the VPAC2 receptor has been shown to localize to primary cilia both in neurons and glial cells, malfunction of which is known to participate in neurological deficits [31]. Rare CNVs (copy number gains) at chromosome 7q36.3 were found to significantly associate with schizophrenia, which results in increased VPAC2 mRNA and cyclic AMP signaling in cultured lymphocytes from patients [32] (Table 44.1).

It should be noted that there are independent studies that do not replicate these associations [37, 38]. These clinical findings need further replication and investigation to clarify their functional importance.

Mechanistic Perspectives and Outlook

The exact mechanisms for PACAP-dependent psychomotor regulation remain to be determined, but several potential mechanisms have been proposed.

Abnormalities in PACAP-deficient mice show clear responses to environmental conditions during their juvenile stage with increased aggressiveness by isolation rearing and amelioration of hyperactivity, jumping behavior, depression-like behavior, and decreased social interaction by enriched environmental rearing [12]. Pharmacological studies have shown that PACAP heterozygous mutant mice show an exaggerated head-twitch response and prepulse inhibition disruption induced by the serotonin 2 agonist and hallucinogenic drug (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) [33] and PACAP-deficient mice show diminished hypothermic response to serotonin 1A agonists [16]. Furthermore, the forced swim test-induced c-Fos expression was markedly blunted in several stress-related brain areas including the dorsal raphe nucleus and the bed nucleus of the stria terminalis in PACAP-deficient mice [14]. These results further support the validity of PACAP-deficient mice as an animal model to investigate mechanisms underlying gene-environment interactions and aberrant regulation of serotonergic function and neuronal plasticity (Fig. 44.1).

Disrupted-In-Schizophrenia 1 (DISC1) is a risk gene candidate for major psychiatric disorders. PACAP markedly decreases the association between DISC1 and DISC1-binding zinc finger protein (DBZ) leading to enhanced neurite outgrowth [34]. Increased expression of stathmin 1 induces abnormal arborization of axons in primary cultured hippocampal neurons. In PACAP-deficient mice, stathmin 1 is upregulated in the dentate gyrus at both the mRNA and protein levels [35]. In an independent study, stathmin 1 has been shown to be involved in the neurotrophic effect of PACAP in PC12 cells [36]. These results propose possible molecular mechanisms for altered PACAP signaling leading to abolished neuronal circuits and behavioral and neurophysiological abnormalities [9].

Although the results described above and in other literature provide diversified and dispersed features for the etiological mechanisms, taken collectively, the convergent evidence from animal models and clinical studies suggest that PACAP signaling can be an intrinsic regulator of psychoneurological functions and may propose an attractive therapeutic target for psychiatric disorders (Fig. 44.1).