Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

Prenatal antidepressant exposure and emotional disorders until age 22: a danish register study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants in pregnancy. Animal and some clinical studies have suggested potential increases in depression and anxiety following prenatal SSRI exposure, but the extent to which these are driven by the medication remains unclear. We used Danish population data to test associations between maternal SSRI use during pregnancy and children outcomes up to age 22. METHODS: We prospectively followed 1,094,202 single-birth Danish children born 1997-2015. The primary exposure was ≥ 1 SSRI prescription filled during pregnancy; the primary outcome, first diagnosis of a depressive, anxiety, or adjustment disorder, or redeemed prescription for an antidepressant medication. We used propensity score weights to adjust potential confounders, and incorporated data from the Danish National Birth Cohort (1997-2003) to further quantify potential residual confounding by subclinical factors. RESULTS: The final dataset included 15,651 exposed and 896,818 unexposed, children. After adjustments, SSRI-exposed had higher rates of the primary outcome than those of mothers who either did not use an SSRI (HR = 1.55 [95%CI:1.44,1.67] or discontinued the SSRI use ≥ 3 months prior to conception (HR = 1.23 [1.13,1.34]). Age of onset was earlier among exposed (9 [IQR:7-13] years) versus unexposed (12 [IQR:12-17] years) children (p < 0.01). Paternal SSRI use in the absence of maternal use during the index pregnancy (HR = 1.46 [1.35,1.58]) and maternal SSRI use only after pregnancy (HR = 1.42 [1.35,1.49]) were each also associated with these outcomes. CONCLUSIONS: While SSRI exposure was associated with increased risk in the children, this risk may be driven at least partly by underlying severity of maternal illness or other confounding factors.

Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine.

Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs.

Intra-session test-retest reliability of functional connectivity in infants.

Resting functional MRI studies of the infant brain are increasingly becoming an important tool in developmental neuroscience. Whereas the test-retest reliability of functional connectivity (FC) measures derived from resting fMRI data have been characterized in the adult and child brain, similar assessments have not been conducted in infants. In this study, we examined the intra-session test-retest reliability of FC measures from 119 infant brain MRI scans from four neurodevelopmental studies. We investigated edge-level and subject-level reliability within one MRI session (between and within runs) measured by the Intraclass correlation coefficient (ICC). First, using an atlas-based approach, we examined whole-brain connectivity as well as connectivity within two common resting fMRI networks - the default mode network (DMN) and the sensorimotor network (SMN). Second, we examined the influence of run duration, study site, and scanning manufacturer (e.g., Philips and General Electric) on ICCs. Lastly, we tested spatial similarity using the Jaccard Index from networks derived from independent component analysis (ICA). Consistent with resting fMRI studies from adults, our findings indicated poor edge-level reliability (ICC = 0.14-0.18), but moderate-to-good subject-level intra-session reliability for whole-brain, DMN, and SMN connectivity (ICC = 0.40-0.78). We also found significant effects of run duration, site, and scanning manufacturer on reliability estimates. Some ICA-derived networks showed strong spatial reproducibility (e.g., DMN, SMN, and Visual Network), and were labelled based on their spatial similarity to analogous networks measured in adults. These networks were reproducibly found across different study sites. However, other ICA-networks (e.g. Executive Control Network) did not show strong spatial reproducibility, suggesting that the reliability and/or maturational course of functional connectivity may vary by network. In sum, our findings suggest that developmental scientists may be on safe ground examining the functional organization of some major neural networks (e.g. DMN and SMN), but judicious interpretation of functional connectivity is essential to its ongoing success.

Depression Risk Is Associated With Weakened Synchrony Between the Amygdala and Experienced Emotion.

BACKGROUND: Major depressive disorder (MDD) is associated with aberrant limbic neural responses to emotional stimuli. We assessed how self-generated emotions modulate trial-by-trial limbic activity and whether this brain-emotion synchrony varies by familial MDD risk (regardless of personal MDD history) and neuroticism. METHODS: Participants (n = 74, mean age = 34 years) were later-generation family members of depressed or nondepressed probands as part of a longitudinal cohort study. Using an emotion induction task, we examined participant-specific modulation of anatomically defined limbic neurobiology. Neuroticism, mental health, and familial parenting style were assessed, and MDD assessments were routinely collected throughout the previous longitudinal assessments of the study. RESULTS: Participant-specific emotional arousal modulated amygdala and hippocampal activity. Lasso regression identified attenuated right amygdala arousal modulation as being relatively more associated with neuroticism (even though neuroticism was not associated with arousal ratings). Attenuated amygdala modulation and neuroticism were significantly more likely in offspring of parents with MDD. Parental MDD, but not personal history of MDD, predicted attenuated amygdala modulation. CONCLUSIONS: Attenuated right amygdala modulation by emotional arousal was associated with neuroticism, indicating that the amygdala was less synchronous with emotional experiences in individuals higher in neuroticism. This neurophenotype was predicted by participants' parental MDD history but not by their own MDD history; that is, it was observed in unaffected and affected offspring of parents with MDD. These data suggest that weak amygdala-emotion synchrony may be a predisposing risk factor for MDD, rather than a result of the illness, and they suggest pathways by which this risk factor for depression is passed intergenerationally.

5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy.

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find that 5-HT2C receptor antagonism potentiates the antidepressant and anxiolytic effects of SSRIs. Together our findings demonstrate opposing roles for 5-HT2C receptors in the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists for both reduction of motor side effects of SSRIs and augmentation of therapeutic antidepressant and anxiolytic effects.

Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis.

Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.

5-HT2A receptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression.

Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin2A receptor (5-HT2A) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT2A receptor knockout (5-HT2A -/-) mice of both sexes. Methods: 5-HT2A -/- and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT2A -/- mice of both sexes. 5-HT2A -/- female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT2A -/- male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor (Bdnf), Egr2, Egr4, FBJ osteosarcoma gene (Fos), FBJ murine osteosarcoma viral oncogene homolog B (Fosb), Fos-like antigen 2 (Fosl2), Homer scaffolding protein (Homer) 1-3 (Homer1-3), Jun proto-oncogene (Jun)) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT2A receptor deficiency. However, the loss of function of the 5-HT2A receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner.

Adult outcomes of childhood disruptive disorders in offspring of depressed and healthy parents.

BACKGROUND: Longitudinal studies of children with disruptive disorders (DDs) have shown high rates of antisocial personality disorder (ASPD) and substance use in adulthood, but few have examined the contribution of parental disorders. We examine child-/adulthood outcomes of DDs in offspring, whose biological parents did not have a history of ASPD, bipolar disorder, or substance use disorders. METHOD: Offspring (N = 267) of parents with or without major depression (MDD), but no ASPD or bipolar disorders were followed longitudinally over 33 years, and associations between DDs and psychiatric and functional outcomes were tested. RESULTS: Eighty-nine (33%) offspring had a DD. Those with, compared to without DDs, had higher rates of MDD (adjusted odds ratio, AOR = 3.42, p < 0.0001), bipolar disorder (AOR = 3.10, p = 0.03), and substance use disorders (AOR = 5.69, p < 0.0001) by age 18, as well as poorer school performance and global functioning. DDs continued to predict MDD and substance use outcomes in adulthood, even after accounting for presence of the corresponding disorder in childhood (MDD: hazards ratio, HR = 3.25, p < 0.0001; SUD, HR = 2.52, p < 0.0001). Associations were similar among the offspring of parents with and without major depression. DDs did not predict adulthood ASPD in either group. LIMITATIONS: Associations are largely accounted for by conduct disorder (CD), as there were few offspring with ADHD, and oppositional defiant disorder (ODD) was not diagnosed at the time this study began. CONCLUSION: If there is no familial risk for ASPD, bipolar disorder or substance use, childhood DDs do not lead to ASPD in adulthood; however, the children still have poorer prognosis into midlife. Early treatment of children with DD, particularly CD, while carefully considering familial risk for these disorders, may help mitigate later adversity.

Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy.

Importance: Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed. Objective: To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI). Design, Setting, and Participants: A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016. Exposures: Selective serotonin reuptake inhibitors and untreated maternal depression. Main Outcomes and Measures: Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography. Results: The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (P < .05; whole-brain correction). In connectome-level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (P < .05; whole connectome correction). Conclusions and Relevance: Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes.

Effects of Serotonin Transporter Gene Variation on Impulsivity Mediated by Default Mode Network: A Family Study of Depression.

Serotonergic neurotransmission, potentially through effects on the brain's default mode network (DMN), may regulate aspects of attention including impulse control. Indeed, genetic variants of the serotonin transporter (5-HTT) have been implicated in impulsivity and related psychopathology. Yet it remains unclear the mechanism by which the 5-HTT genetic variants contribute to individual variability in impulse control. Here, we tested whether DMN connectivity mediates an association between the 5-HTT genetic variants and impulsivity. Participants (N = 92) were from a family cohort study of depression in which we have previously shown a broad distribution of 5-HTT variants. We genotyped for 5-HTTLPR and rs25531 (stratified by transcriptional efficiency: 8 low/low, 53 low/high, and 31 high/high), estimated DMN structural connectivity using diffusion probabilistic tractography, and assessed behavioral measures of impulsivity (from 12 low/low, 48 low/high, and 31 high/high) using the Continuous Performance Task. We found that low transcriptional efficiency genotypes were associated with decreased connection strength between the posterior DMN and the superior frontal gyrus (SFG). Path modeling demonstrated that decreased DMN-SFG connectivity mediated the association between low-efficiency genotypes and increased impulsivity. Taken together, this study suggests a gene-brain-behavior pathway that perhaps underlies the role of the serotonergic neuromodulation in impulse control.

New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain.

Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system (CNS) development, such sensitive periods shape the formation of neuro-circuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint, as well as the environmental context. While allowing for adaptation, such sensitive periods are also windows of vulnerability during which external and internal factors can confer risk to brain disorders by derailing adaptive developmental programs. Our group has been particularly interested in developmental periods that are sensitive to serotonin (5-HT) signaling, and impact behavior and cognition relevant to psychiatry. Specifically, we review a 5-HT-sensitive period that impacts fronto-limbic system development, resulting in cognitive, anxiety, and depression-related behaviors. We discuss preclinical data to establish biological plausibility and mechanistic insights. We also summarize epidemiological findings that underscore the potential public health implications resulting from the current practice of prescribing 5-HT reuptake inhibiting antidepressants during pregnancy. These medications enter the fetal circulation, likely perturb 5-HT signaling in the brain, and may be affecting circuit maturation in ways that parallel our findings in the developing rodent brain. More research is needed to better disambiguate the dual effects of maternal symptoms on fetal and child development from the effects of 5-HT reuptake inhibitors on clinical outcomes in the offspring. Birth Defects Research 109:924-932, 2017. © 2017 Wiley Periodicals, Inc.

5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress.

Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT2A receptor knockout (5-[Formula: see text]) and wild-type mice of both sexes. While 5-[Formula: see text] male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-[Formula: see text] female mice with a hyperlipidemic baseline phenotype. 5-[Formula: see text] male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-[Formula: see text] mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic.

Associations between serotonin transporter and behavioral traits and diagnoses related to anxiety.

The role of the serotonin transporter promoter-linked polymorphism (5-HTTLPR) in psychiatric disease remains unclear. Behavioral traits could serve as alternative outcomes that are stable, precede psychopathology, and capture more sub-clinical variation. We test associations between 5-HTTLPR and (1) behavioral traits and (2) clinical diagnoses of anxiety and depression. Second and third generation participants (N=203, 34.2±13.8 years, 54% female) at high- or low- familial risk for depression (where risk was defined by the presence of major depression in the 1st generation) were assessed longitudinally using the Schedule for Affective Disorders and Schizophrenia-lifetime interview, Barratt Impulsiveness Scale-11, Buss-Perry Aggression Questionnaire, and the NEO-Five Factor Inventory. High (but not low)-risk offspring with two risk (short, s) alleles had higher impulsivity (+13%), hostility (+31%) and neuroticism (+23%). SS was associated higher rates of panic (OR=7.05 [2.44, 20.38], p=0.0003) and phobic (OR=2.68[1.04, 6.93], p=0.04), but not other disorders. Impulsivity accounted for 16% of associations between 5-HTTLPR and panic, and 52% of association between 5-HTTLPR and phobias. We show that 5-HTTLPR predicts higher impulsivity, hostility, and neuroticism, and that impulsivity could serve as a useful independent outcome or intermediary phenotype in genetic studies of anxiety.

Developmental expression of mGlu2 and mGlu3 in the mouse brain.

The glutamatergic system directs central nervous system (CNS) neuronal activity and may underlie various neuropsychiatric disorders. Glutamate transmits its effects through multiple receptor classes. Class II metabotropic glutamate receptors, mGlu2 and mGlu3, play an important role in regulating synaptic release of different neurotransmitter systems and consequently modulate signaling across several neuronal subtypes. Drugs targeting mGlu2 and mGlu3 are seen as potential therapeutics for various psychiatric and neurological disorders, and defining their expression through development can aid in understanding their distinct function. Here, non-radioactive in situ hybridization was used to detect mGlu2 and mGlu3 mRNA in the CNS of 129SvEv mice at PN1, PN8, PN25, PN40, and PN100. At PN1, mGlu2 and mGlu3 are strongly expressed cortically, most notably in layer III and V. Subcortically, mGlu2 is detected in thalamic nuclei; mGlu3 is highly expressed in the striatum. By PN8, the most notable changes are in hippocampus and cortex, with mGlu2 densely expressed in the dentate gyrus, and showing increased cortical levels especially in medial cortex. At PN8, mGlu3 is observed in cortex and striatum, with highest levels detected in reticular thalamic nucleus. At PN25 patterns of expression approximated those observed across adulthood (PN40 & PN100): mGlu2 expression was high in cortex and dentate gyrus while mGlu3 showed expression in the reticular thalamic nucleus, cortex, and striatum. These studies provide a foundation for future research seeking to parse out the roles of mGlu2 from mGlu3, paving the way for better understanding of how these receptors regulate activity in the brain.

Association of Selective Serotonin Reuptake Inhibitor Exposure During Pregnancy With Speech, Scholastic, and Motor Disorders in Offspring.

IMPORTANCE: Speech/language, scholastic, and motor disorders are common in children. It is unknown whether exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy influences susceptibility to these disorders. OBJECTIVE: To examine whether SSRI exposure during pregnancy is associated with speech/language, scholastic, and motor disorders in offspring up to early adolescence. DESIGN, SETTING, AND PARTICIPANTS: This prospective birth cohort study examined national population-based register data in Finland from 1996 to 2010. The sampling frame includes 845 345 pregnant women and their singleton offspring with data on maternal use of antidepressants and depression-related psychiatric disorders during pregnancy. EXPOSURES: There were 3 groups of offspring: 15 596 were in the SSRI-exposed group, ie, had mothers diagnosed as having depression-related psychiatric disorders with a history of purchasing SSRIs during pregnancy; 9537 were in the unmedicated group, ie, had mothers diagnosed as having depression-related psychiatric disorders without a history of purchasing SSRIs during pregnancy; and 31 207 were in the unexposed group, ie, had mothers without a psychiatric diagnosis or a history of purchasing SSRIs. MAIN OUTCOMES AND MEASURES: Cumulative incidence of speech/language, scholastic, or motor disorders (829, 187, and 285 instances, respectively) from birth to 14 years. All hypotheses tested were formulated before data collection. RESULTS: Of the 56 340 infants included in the final cohort, 28 684 (50.9%) were male and 48 782 (86.6%) were 9 years or younger. The mean (SD) ages of children at diagnosis were 4.43 (1.67), 3.55 (2.67), and 7.73 (2.38) for speech/language, scholastic, and motor disorders, respectively. Offspring of mothers who purchased SSRIs at least twice during pregnancy had a significant 37% increased risk of speech/language disorders compared with offspring in the unmedicated group. The cumulative hazard of speech/language disorders was 0.0087 in the SSRI-exposed group vs 0.0061 in the unmedicated group (hazard ratio, 1.37; 95% CI, 1.11-1.70; P = .004). There was a significantly increased risk of these disorders in offspring in the SSRI-exposed and unmedicated groups compared with offspring in the unexposed group. For scholastic and motor disorders, there were no differences between offspring in the SSRI-exposed group and in the unmedicated group. CONCLUSIONS AND RELEVANCE: Exposure to SSRIs during pregnancy was associated with an increased risk of speech/language disorders. This finding may have implications for understanding associations between SSRIs and child development.

Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders: A National Register-Based Study.

OBJECTIVE: To investigate the impact of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on offspring neurodevelopment. METHOD: This is a cohort study using national register data in Finland between the years 1996 and 2010. Pregnant women and their offspring were categorized into 4 groups: SSRI exposed (n = 15,729); exposed to psychiatric disorder, no antidepressants (n = 9,651); exposed to SSRIs only before pregnancy (n = 7,980); and unexposed to antidepressants and psychiatric disorders (n = 31,394). We investigated the cumulative incidence of offspring diagnoses of depression, anxiety, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) for the 4 groups from birth to 14 years, adjusting for confounders. RESULTS: The cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2% (95% CI = 3.1-13.3%) by age 14.9 years, compared with 1.9% (95% CI = 0.9-2.9%) in the psychiatric disorder, no medication group (adjusted hazard ratio [HR] = 1.78; 95% CI = 1.12-2.82; p = .02) and to 2.8% (95% CI = 1.4-4.3%) in the SSRI discontinued group (HR = 1.84; 95% CI = 1.14-2.97; p = .01). Rates of anxiety, ASD, and ADHD diagnoses were comparable to rates in offspring of mothers with a psychiatric disorder but no medication during pregnancy. Comparing SSRI exposed to unexposed individuals, the HRs were significantly elevated for each outcome. CONCLUSION: Prenatal SSRI exposure was associated with increased rates of depression diagnoses in early adolescence but not with ASD or ADHD. Until confirmed, these findings must be balanced against the substantial adverse consequences of untreated maternal depression.

5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists.

In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) ß subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP-809,101 and antagonist SB-242,084 increase mitochondrial genes and oxidative metabolism through the 5-HT2A receptor. To our knowledge, this is the first report that links 5-HT2A receptor agonism to mitochondrial function.

Serotonin signaling modulates the effects of familial risk for depression on cortical thickness.

Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The "s" allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.

Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors.

Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 µM) and high (100 µM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 µM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 µM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 µM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre-synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G-protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and thus facilitating GABA release.