Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.

Pattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2.

Sociability is crucial for survival, whereas social avoidance is a feature of disorders such as Rett syndrome, which is caused by loss-of-function mutations in MECP2. To understand how a preference for social interactions is encoded, we used in vivo calcium imaging to compare medial prefrontal cortex (mPFC) activity in female wild-type and Mecp2-heterozygous mice during three-chamber tests. We found that mPFC pyramidal neurons in Mecp2-deficient mice are hypo-responsive to both social and nonsocial stimuli. Hypothesizing that this limited dynamic range restricts the circuit's ability to disambiguate coactivity patterns for different stimuli, we suppressed the mPFC in wild-type mice and found that this eliminated both pattern decorrelation and social preference. Conversely, stimulating the mPFC in MeCP2-deficient mice restored social preference, but only if it was sufficient to restore pattern decorrelation. A loss of social preference could thus indicate impaired pattern decorrelation rather than true social avoidance.

Lifelong consequences of brain injuries during development: From risk to resilience.

Traumatic brain injuries in children represent a major public health issue and even relatively mild injuries can have lifelong consequences. However, the outcomes from these injuries are highly heterogeneous, with most individuals recovering fully, but a substantial subset experiencing prolonged or permanent disabilities across a number of domains. Moreover, brain injuries predispose individuals to other kinds of neuropsychiatric and somatic illnesses. Critically, the severity of the injury only partially predicts subsequent outcomes, thus other factors must be involved. In this review, we discuss the psychological, social, neuroendocrine, and autonomic processes that are disrupted following traumatic brain injury during development, and consider the mechanisms the mediate risk or resilience after traumatic brain injury in this vulnerable population.

Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein.

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Melanocortin 4 receptor stimulation improves social deficits in mice through oxytocin pathway.

Several studies on humans and mice support oxytocin's role in improving social behaviour, but its use in pharmacotherapy presents some important limiting factors. To date, it is emerging a pharmacological potential for melanocortin 4 receptor (MC4R) agonism in social deficits treatment. Recently, we demonstrated that the deletion of the NFKB1 gene, which encodes the p50 NF-κB subunit, causes impairment in social behaviours, with reductions in social interactions in mice. In this work, we tested the acute effects of THIQ, a selective melanocortin 4 receptor (MC4R) agonist. THIQ treatment increased social interactions both in wild type and p50-/- mice. In particular, after treatment with THIQ, p50-/- mice showed a prosocial behaviour analogous to that of basal WT mice. Moreover, intranasal treatment with an oxytocin antagonist blocked social interactions induced by THIQ, demonstrating that its prosocial effects are mediated by the oxytocin pathway. The data obtained reinforce using MC4R agonists to ameliorate social impairment in NDDs.

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia.

Depression and anxiety are the most common psychiatric disorders, representing a major public health concern. Dysregulation of oxidative and inflammatory systems may be associated with psychiatric disorders, such as depression and anxiety. Due to the need to find appropriate animal models to the understanding of such disorders, we queried whether 2 BXD recombinant inbred (RI) mice strains (BXD21/TyJ RI and BXD84/RwwJ RI mice) and C57BL/6 wild-type mice show differential performance in depression and anxiety related behaviors and biomarkers. Specifically, we assessed social preference, elevated plus maze, forced swim, and Von Frey tests at 3-4 months-of-age, as well as activation of cytokines and antioxidant mRNA levels in the cortex at 7 months-of-age. We report that (1) the BXD84/RwwJ RI strain exhibits anxiety disorder and social avoidance-like behavior (2) BXD21/TyJ RI strain shows a resistance to depression illness, and (3) sex-dependent cytokine profiles and allodynia with elevated inflammatory activity were inherent to male BXD21/TyJ RI mice. In conclusion, we provide novel data in favor of the use of BXD recombinant inbred mice to further understand anxiety and depression disorders.

Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice.

Several genome- and proteome-wide studies have associated transcription and translation changes of CRMP2 (collapsing response mediator protein 2) with psychiatric disorders, yet little is known about its function in the developing or adult mammalian brain in vivo. Here we show that brain-specific Crmp2 knockout (cKO) mice display molecular, cellular, structural and behavioural deficits, many of which are reminiscent of neural features and symptoms associated with schizophrenia. cKO mice exhibit enlarged ventricles and impaired social behaviour, locomotor activity, and learning and memory. Loss of Crmp2 in the hippocampus leads to reduced long-term potentiation, abnormal NMDA receptor composition, aberrant dendrite development and defective synapse formation in CA1 neurons. Furthermore, knockdown of crmp2 specifically in newborn neurons results in stage-dependent defects in their development during adult hippocampal neurogenesis. Our findings reveal a critical role for CRMP2 in neuronal plasticity, neural function and behavioural modulation in mice.

Effects of pterostilbene and resveratrol on brain and behavior.

Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 4'-trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and anti-inflammatory signaling and behavioral outcomes.

Hyperactivity and lack of social discrimination in the adolescent Fmr1 knockout mouse.

The aims of this study were to investigate behaviour relevant to human autism spectrum disorder (ASD) and the fragile X syndrome in adolescent Fmr1 knockout (KO) mice and to evaluate the tissue levels of striatal monoamines. Fmr1 KO mice were evaluated in the open field, marble burying and three-chamber test for the presence of hyperactivity, anxiety, repetitive behaviour, sociability and observation of social novelty compared with wild-type (WT) mice. The Fmr1 KO mice expressed anxiety and hyperactivity in the open field compared with WT mice. This increased level of hyperactivity was confirmed in the three-chamber test. Fmr1 KO mice spent more time with stranger mice compared with the WT. However, after a correction for hyperactivity, their apparent increase in sociability became identical to that of the WT. Furthermore, the Fmr1 KO mice could not differentiate between a familiar or a novel mouse. Monoamines were measured by HPLC: Fmr1 KO mice showed an increase in the striatal dopamine level. We conclude that the fragile X syndrome model seems to be useful for understanding certain aspects of ASD and may have translational interest for studies of social behaviour when hyperactivity coexists in ASD patients.

Improvement of ketamine-induced social withdrawal in rats: the role of 5-HT7 receptors.

Social withdrawal, one of the core negative symptoms of schizophrenia, can be modelled in the social interaction (SI) test in rats using N-methyl-D-aspartate receptor glutamate receptor antagonists. We have recently shown that amisulpride, an antipsychotic with a high affinity for serotonin 5-HT7 receptors, reversed ketamine-induced SI deficits in rats. The aim of the present study was to further elucidate the potential involvement of 5-HT7 receptors in the prosocial action of amisulpride. Acute administration of amisulpride (3 mg/kg) and SB-269970 (1 mg/kg), a 5-HT7 receptor antagonist, reversed ketamine-induced social withdrawal, whereas sulpiride (20 or 30 mg/kg) and haloperidol (0.2 mg/kg) were ineffective. The 5-HT7 receptor agonist AS19 (10 mg/kg) abolished the prosocial efficacy of amisulpride (3 mg/kg). The coadministration of an inactive dose of SB-269970 (0.2 mg/kg) showed the prosocial effects of inactive doses of amisulpride (1 mg/kg) and sulpiride (20 mg/kg). The anxiolytic chlordiazepoxide (2.5 mg/kg) and the antidepressant fluoxetine (2.5 mg/kg) were ineffective in reversing ketamine-induced SI deficits. The present study suggests that the antagonism of 5-HT7 receptors may contribute towards the mechanisms underlying the prosocial action of amisulpride. These results may have therapeutic implications for the treatment of negative symptoms in schizophrenia and other disorders characterized by social withdrawal.

Genes showing altered expression in the medial preoptic area in the highly social maternal phenotype are related to autism and other disorders with social deficits.

BACKGROUND: The mother-child relationship is the most fundamental social bond in mammals, and previous studies indicate that the medial preoptic area (MPOA) contributes to this increase in sociability. It is possible that the same genes that lead to elevated sociability in one condition (the maternal state) might also be dysregulated in some disorders with social deficits (e.g. autism). In this study, we examined whether there was enrichment (greater than chance overlap) for social deficit disorder related genes in MPOA microarray results between virgin and postpartum female mice. We utilized microarrays to assess large scale gene expression changes in the MPOA of virgin and postpartum mice. The Modular Single Set Enrichment Test (MSET) was used to determine if mental health disorder related genes were enriched in significant microarray results. Additional resources, such as ToppCluster, NIH DAVID, and weighted co-expression network analysis (WGCNA) were used to analyze enrichment for specific gene clusters or indirect relationships between significant genes of interest. Finally, a subset of microarray results was validated using quantitative PCR. RESULTS: Significant postpartum MPOA microarray results were enriched for multiple disorders that include social deficits, including autism, bipolar disorder, depression, and schizophrenia. Together, 98 autism-related genes were identified from the significant microarray results. Further, ToppCluser and NIH DAVID identified a large number of postpartum genes related to ion channel activity and CNS development, and also suggested a role for microRNAs in regulating maternal gene expression. WGCNA identified a module of genes associated with the postpartum phenotype, and identified indirect links between transcription factors and other genes of interest. CONCLUSION: The transition to the maternal state involves great CNS plasticity and increased sociability. We identified multiple novel genes that overlap between the postpartum MPOA (high sociability) and mental health disorders with low sociability. Thus, the activity or interactions of the same genes may be altering social behaviors in different directions in different conditions. Maternity also involves elevated risks for disorders, including depression, psychosis, and BPD, so identification of maternal genes common to these disorders may provide insights into the elevated vulnerability of the maternal brain.

Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism.

Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

The response to sulpiride in social anxiety disorder: D2 receptor function.

Some previous studies have suggested that patients with social anxiety disorder (SAD) have a hypoactive central dopaminergic system. Supporting this there have been reports from neuroimaging studies of reduced striatal D2 receptor binding in subjects with SAD. The aim of this study was to investigate D2 receptor sensitivity in patients with SAD compared with a group of matched, healthy controls using a neuroendocrine challenge with the selective D2 antagonist, sulpiride. D2 receptor function was assessed in 23 subjects with generalized SAD and 23 matched, healthy controls using a challenge with 400 mg of a selective D2 antagonist, sulpiride in a randomized, placebo-controlled, crossover design. Response to sulpiride was measured by the change in prolactin level and changes in self-rated measures of social anxiety, mood and the ability to experience pleasure. There was no significant difference in prolactin response to sulpiride between the two groups. Sulpiride resulted in no effect in either the SAD or healthy control group on measures of social anxiety, mood or the ability to experience pleasure. Contrary to our hypothesis, in this study we found no evidence of reduced D2 receptor function in subjects with SAD compared with healthy controls.

Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53.

Etiology of aberrant social behavior consistently points to a strong polygenetic component involved in fundamental developmental pathways, with the potential of being enhanced by defects in bioenergetics. To this end, the occurrence of social deficits and mitochondrial outcomes were evaluated in conditional Pten (Phosphatase and tensin homolog) haplo-insufficient mice, in which only one allele was selectively knocked-out in neural tissues. Pten mutations have been linked to Alzheimer's disease and syndromic autism spectrum disorders, among others. By 4-6 weeks of age, Pten insufficiency resulted in the increase of several mitochondrial Complex activities (II-III, IV and V) not accompanied by increases in mitochondrial mass, consistent with an activation of the PI3K/Akt pathway, of which Pten is a negative modulator. At 8-13 weeks of age, Pten haplo-insufficient mice did not show significant behavioral abnormalities or changes in mitochondrial outcomes, but by 20-29 weeks, they displayed aberrant social behavior (social avoidance, failure to recognize familiar mouse, and repetitive self-grooming), macrocephaly, increased oxidative stress, decreased cytochrome c oxidase (CCO) activity (50%) and increased mtDNA deletions in cerebellum and hippocampus. Mitochondrial dysfunction was the result of a downregulation of p53-signaling pathway evaluated by lower protein expression of p21 (65% of controls) and the CCO chaperone SCO2 (47% of controls), two p53-downstream targets. This mechanism was confirmed in Pten-deficient striatal neurons and, HCT 116 cells with different p53 gene dosage. These results suggest a unique pathogenic mechanism of the Pten-p53 axis in mice with aberrant social behavior: loss of Pten (via p53) impairs mitochondrial function elicited by an early defective assembly of CCO and later enhanced by the accumulation of mtDNA deletions. Consistent with our results, (i) SCO2 deficiency and/or CCO activity defects have been reported in patients with learning disabilities including autism and (ii) mutated proteins in ASD have been found associated with p53-signaling pathways.

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP-ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD.

Child µ-opioid receptor gene variant influences parent-child relations.

Variation in the µ-opioid receptor gene has been associated with early social behavior in mice and rhesus macaques. The current study tested whether the functional OPRM1 A118G predicted various indices of social relations in children. The sample included 226 subjects of self-reported European ancestry (44% female; mean age 13.6, SD=2.2) who were part of a larger representative study of children aged 9-17 years in rural North Carolina. Multiple aspects of recent (past 3 months) parent-child relationship were assessed using the Child and Adolescent Psychiatric Assessment. Parent problems were coded based upon a lifetime history of mental health problems, substance abuse, or criminality. Child genotype interacted with parent behavior such that there were no genotype differences for those with low levels of parent problems; however, when a history of parent problems was reported, the G allele carriers had more enjoyment of parent-child interactions (mean ratio (MR)=3.5, 95% CI=1.6, 8.0) and fewer arguments (MR=3.1, 95% CI=1.1, 8.9). These findings suggest a role for the OPRM1 gene in the genetic architecture of social relations in humans. In summary, a variant in the µ-opioid receptor gene (118G) was associated with improved parent-child relations, but only in the context of a significant disruption in parental functioning.

[Vulnerability of dopamine circuit development to cytokines from the periphery: implication in schizophrenia].

Epidermal growth factor (EGF) and neuregulin-1 (NRG) belong to the ErbB ligand family and both exert neurotrophic actions on midbrain dopamine neurons. According to the immune inflammatory hypothesis for schizophrenia, we have established rodent models for this illness by exposing their neonates to these cytokines. At post-pubertal stage, these animals develop various neurobehavioral abnormalities such as prepulse inhibition (PPI) and social interaction deficits. In this review, we introduce neurochemical features of the EGF-treated rats and NRG-treated mice, which exhibit persistent increases in tyrosine hydroxylase levels and dopamine release in the globus pallidus and prelimbic cortex (medial prefrontal cortex), respectively. Local blockade of the hyperdopaminergic state in EGF-treated rats ameliorates their behavioral deficits. These findings suggest that development of the midbrain dopamine system is vulnerable to circulating cytokines at perinatal and/or prenatal stages and potentially influences schizophrenia risk or neuropathology. The dopamine hypothesis for schizophrenia is re-evaluated with the obtained results as well as with published literatures in this review.

Self-regulatory deficits in fibromyalgia and temporomandibular disorders.

Chronic pain conditions such as fibromyalgia (FM) and temporomandibular disorders (TMDs) are accompanied by complex interactions of cognitive, emotional, and physiological disturbances. Such conditions are complicated and draining to live with, and successful adaptation may depend on ability to self-regulate. Self-regulation involves capacity to exercise control and guide or alter reactions and behavior, abilities essential for human adjustment. Research indicates that self-regulatory strength is a limited source that can be depleted or fatigued, however, and the current study aimed to show that patients with FM and TMD are vulnerable to self-regulatory fatigue as a consequence of their condition. Patients (N=50) and pain-free matched controls (N=50) were exposed to an experimental self-regulation task followed by a persistence task. Patients displayed significantly less capacity to persist on the subsequent task compared with controls. In fact, patients exposed to low self-regulatory effort displayed similar low persistence to patients and controls exposed to high self-regulatory effort, indicating that patients with chronic pain conditions may be suffering from chronic self-regulatory fatigue. Baseline heart rate variability, blood glucose, and cortisol predicted persistence, more so for controls than for patients, and more so in the low vs. high self-regulation condition. Impact of chronic pain conditions on self-regulatory effort was mediated by pain, but not by any other factors. The current study suggests that patients with chronic pain conditions likely suffer from chronic self-regulatory fatigue, and underlines the importance of taking self-regulatory capacity into account when aiming to understand and treat these complex conditions.

Social conceptual impairments in frontotemporal lobar degeneration with right anterior temporal hypometabolism.

Inappropriate social behaviours are early and distinctive symptoms of the temporal and frontal variants of frontotemporal lobar degeneration (FTLD). Knowledge of social behaviour is essential for appropriate social conduct. It is unknown, however, in what way this knowledge is degraded in FTLD. In a recent functional MRI study, we have identified a right-lateralized superior anterior temporal lobe (aTL) region showing selective activation for 'social concepts' (i.e. concepts describing social behaviour: e.g. 'polite', 'stingy') as compared with concepts describing less socially relevant animal behaviour ('animal function concepts': e.g. 'trainable', 'nutritious'). In a further fMRI study, superior aTL activation was independent of the context of actions and feelings associated with these social concepts. Here, we investigated whether the right superior sector of the aTL is necessary for context-independent knowledge of social concepts. We assessed neuronal glucose uptake using 18-fluoro-deoxy-glucose-positron emission tomography (FDG-PET) and a novel semantic discrimination task which probed knowledge of social and animal function concepts in patients with FTLD (n = 29) and corticobasal syndrome (n = 18). FTLD and corticobasal syndrome groups performed equally poorly on animal function concepts but FTLD patients showed more pronounced impairments on social concepts than corticobasal syndrome patients. FTLD patients with right superior aTL hypometabolism, as determined on individual ROI analyses, were significantly more impaired on social concepts than on animal function concepts. FTLD patients with selective impairments for social concepts, as determined on individual neuropsychological profiles, showed higher levels of inappropriate social behaviours ('disinhibition') and demonstrated more pronounced hypometabolism in the right superior aTL, the left temporal pole and the right lateral orbitofrontal and dorsomedial prefrontal cortex as compared with FTLD patients showing selective impairments of animal function concepts. Combining both FTLD subgroup analyses, based on anatomical and neuropsychological criteria, by using inclusive masks, revealed the right superior aTL as associated with selective impairments of social concepts in both analyses. These results corroborate the hypothesis that the right aTL is necessary for representing conceptual social knowledge. Further, we provide first evidence for the potential importance of conceptual social knowledge impairments as contributing to behavioural symptoms of FTLD.

Salivary cortisol and suicidal behavior--a follow-up study.

INTRODUCTION: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis is a common finding in major depressive disorder. Similar studies on suicide attempters are less abundant, and the results are divergent. The main aim of the present study was to investigate HPA-axis parameters by the time of a suicide attempt and at follow-up in search for associations between HPA-axis function and suicidal behavior. METHODS: Thirty-five suicide attempters and 16 non-suicidal controls were admitted to a psychiatric ward between the years of 1986 and 1992. Corticotrophin-releasing hormone (CRH) in cerebrospinal fluid and urinary cortisol were obtained for the suicide attempters. The patients were followed up approximately 12 years after the index admission. Cortisol was measured in saliva, and additional suicide attempts and current psychiatric symptoms were registered. RESULTS: At follow-up, evening salivary cortisol was lower in suicide attempters compared to controls. Low cortisol levels at follow-up were associated with severe psychiatric symptoms. Among women, repeated suicide attempts were associated with low morning and lunch salivary cortisol, and in this subgroup we also found significant correlations between salivary cortisol at follow-up, and CRH as well as urinary cortisol at index. CONCLUSION: We found evidence for an association between low HPA-axis activity and suicidal behavior. This could be due to long-lasting and severe psychiatric morbidity, which in turn has exhausted the HPA-axis of these patients. The potential role of hypocortisolism should be given more attention in studies on suicidal patients.