Blood DNA Methylation Levels in the WNT5A Gene Promoter Region: A Potential Biomarker for Agitation in Subjects with Dementia.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) cause a heavy burden for both patient and caregivers. These symptoms are diverse, and their mechanism is still unclear. Agitation is the most common and difficult to treat among BPSD. In recent years, while changes in DNA methylation levels have been receiving attention as a biomarker of aging and dementia, associations with BPSD have not been examined. OBJECTIVE: Focusing on agitation, the objective of the present study was to identify a region where changes in DNA methylation levels are associated with agitation. METHODS: Using genome-wide DNA methylation analysis data for 7 dementia subjects with agitation, 5 dementia subjects without agitation, and 4 normal elderly controls, we determined a signaling pathway in the WNT5A gene promoter region to be associated with agitation. Based on this result, we measured DNA methylation levels in this region for 26 dementia subjects with agitation and 82 dementia subjects without agitation by means of methylation-sensitive high-resolution melting (MS-HRM) analysis. RESULTS: The WNT5A DNA methylation level in dementia subjects with agitation was significantly lower than in those without agitation (p = 0.001). Changes in WNT5A DNA methylation levels were not influenced by age, sex, body mass index, APOE ɛ4, medication, or inflammatory cytokines. CONCLUSION: Our results suggested an association of agitation with Wnt signaling, in particular with changes in WNT5A DNA methylation levels, which could be a potentially useful biomarker for predicting the appearance of agitation. It may contribute to the elucidation of the mechanism of BPSD.

Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor.

Dopamine transporter knockout (DATk) mice are known to demonstrate profound hyperactivity concurrent with elevated (5-fold) extracellular dopamine in the basal ganglia. At the same time, heterozygous DAT mice (DATh) demonstrate a 2-fold increase in dopamine levels yet only a marginal elevation in locomotor activity level. Another model of dopaminergic hyperactivity is the D3 dopamine receptor knockout (D3k) mice, which present only a modest hyperactivity phenotype, predominately manifested as stereotypical behaviors. In the D3k mice, the hyperactivity is also correlated with elevated extracellular dopamine levels (2-fold) in the basal ganglia. Cross-breeding was used to evaluate the functional consequences of the deletion of both genes. In the heterozygous DAT mice, inactivation of the D3R gene (DATh/D3k) resulted in significant hyperactivity and further elevation of striatal extracellular dopamine above levels observed in respective single mutant mice. The decreased weight of DATk mice was evident regardless of the D3 dopamine receptor genotype. In contrast, measures of thermoregulation revealed that the marked hypothermia of DATk mice (-2 °C) was reversed in double knockout mice. Thus, the extracellular dopamine levels elevated by prolonging uptake could be elevated even further by eliminating the D3 receptor. These data also suggest that the hypothermia observed in DATk mice may be mediated through D3 receptors.

Associations of attention distractibility with attention deficit and with variation in the KTN1 gene.

Attention distractibility in a low load visual search experiment with a rare irrelevant distractor could be an objective continuous measure in adulthood that correlates well with the symptoms of attention deficit throughout lifespan. This was studied using a birth cohort representative sample in a longitudinal study. The expected correlations were not found between the distractor cost measured in the experiment in adulthood and the inattention questionnaire scores from ages 15-33. However, the coefficient of variability for RT (CVRT) correlated negatively with self-reported motor restlessness (age 15) and attention deficit (age 25). We suggest that hyperactivity in childhood improved motor control at age 33. Associations with the gene KTN1 rs945270 (found to affect putamen size) were explored. CVRT, motor restlessness at age 15 and attention deficit scores at age 25 were especially low for male C-allele carriers. A possible association with the volume of putamen of individual participants is considered.

An in-depth neurobehavioral characterization shows anxiety-like traits, impaired habituation behavior, and restlessness in male Cryptochrome-deficient mice.

Many psychiatric disorders, for example, anxiety, are accompanied by disturbances of circadian rhythms, including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Conversely, alternations of circadian rhythms are a risk factor for the development of psychiatric disorders. This assumption is supported by animals with clock gene mutations which often display behaviors that resemble human psychiatric disorders. In this study, we performed an in-depth behavioral analysis with male mice lacking the central clock genes Cryptochrome 1 and 2 (Cry1/2-/- ), which are thus unable to express endogenous circadian rhythms. With wild-type and Cry1/2-/- mice, we performed an extensive behavioral analysis to study their cognitive abilities, social behavior, and their expression of depression-like and anxiety-like behavior. While Cry1/2-/- mice showed only mild abnormalities at cognitive and social behavioral levels, they were consistently more anxious than wildtype mice. Anxiety-like behavior was particularly evident in reduced mobility in new environments, altered ability to habituate, compensatory behavior, and consistent restless behavior across many behavioral tests. In line with their anxiety-like behavioral phenotype, Cry1/2-/- mice have higher c-Fos activity in the amygdala after exposure to an anxiogenic stressor than wild-type mice. In our study, we identified Cry1/2-/- mice as animals that qualify as a translational mouse model for anxiety disorder in humans because of its consistent behavior of restlessness, increased immobility, and dysfunctional habituation in new environments.

Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity.

Background: Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. Methods: We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Results: Conventional heterozygous Scn2a knockout mice (Scn2aKO/+) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2aKO/+ mice with CX516. Additionally, Scn2aKO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2aKO/+ mice, with an increase in the gamma band. Conclusions: Scn2aKO/+ mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes.

Disrupting the hippocampal Piwi pathway enhances contextual fear memory in mice.

The Piwi pathway is a conserved gene regulatory mechanism comprised of Piwi-like proteins and Piwi-interacting RNAs, which modulates gene expression via RNA interference and through interaction with epigenetic mechanisms. The mammalian Piwi pathway has been defined by its role in transposon control during spermatogenesis; however, despite an increasing number of studies demonstrating its expression in the nervous system, relatively little is known about its function in neurons or potential contribution to behavioural regulation. We have discovered that all three Piwi-like genes are expressed in the adult mouse brain, and that viral-mediated knockdown of the Piwi-like genes Piwil1 and Piwil2 in the dorsal hippocampus leads to enhanced contextual fear memory without affecting generalised anxiety. These results implicate the Piwi pathway in behavioural regulation in the adult mammalian brain, likely through modulation of plasticity-related gene expression.

Disturbed neurotransmitter homeostasis in ether lipid deficiency.

Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters. In the dopaminergic nigrostriatal tract, synaptic endings but not neuronal cell bodies were affected. Neurotransmitter turnover was altered in ether lipid-deficient murine as well as human post-mortem brain tissue. A generalized loss of synapses did not account for the neurotransmitter deficits, since the levels of several presynaptic proteins appeared unchanged. However, reduced amounts of vesicular monoamine transporter indicate a compromised vesicular uptake of neurotransmitters. As exemplified by norepinephrine, the release of neurotransmitters from Gnpat KO brain slices was diminished in response to strong electrical and chemical stimuli. Finally, addressing potential phenotypic correlates of the disturbed neurotransmitter homeostasis, we show that ether lipid deficiency manifests as hyperactivity and impaired social interaction. We propose that the lack of ether lipids alters the properties of synaptic vesicles leading to reduced amounts and release of neurotransmitters. These features likely contribute to the behavioral phenotype of Gnpat KO mice, potentially modeling some human neurodevelopmental disorders like autism or attention deficit hyperactivity disorder.

Hyperactive and anxiolytic-like behaviors result from loss of COUP-TFI/Nr2f1 in the mouse cortex.

The nuclear receptor COUP TFI (also known as Nr2f1) plays major roles in specifying distinct neuronal subtypes during patterning of the neocortical motor and somatosensory cortex, as well as in regulating the longitudinal growth of the hippocampus during development. In humans, mutations in the NR2F1 gene lead to a global developmental delay and intellectual disabilities. While more than 30% of patients show behavioral features of autism spectrum disorder, 16% of haploinsufficient children show signs of hyperactivity and impulsivity. Loss of COUP-TFI in the cortical mouse primordium results in altered area organization and serotonin distribution, abnormal coordination of voluntary movements and learning and memory deficits. Here, we asked whether absence of COUP-TFI affects locomotor activity, anxiety, as well as depression. Mice mutant for COUP-TFI have normal motor coordination, but significant traits of hyperactivity, which does not seem to respond to N-Methyl-D-aspartate (NMDA) antagonists. However, no changes in anxiety, despite increased locomotor performances, were observed in the open field task. On the contrary, elevated plus maze and dark-light test explorations indicate a decreased anxiety-like behavior in COUP-TFI mutant mice. Finally, significantly reduced immobility in the forced swim test and no changes in anhedonia in the sucrose preference task suggest no particular depressive behaviors in mutant mice. Taken together, our study shows that loss of COUP-TFI leads to increased locomotor activity but less anxiety and contributes in further deciphering the pathophysiology of patients haploinsufficient for NR2F1.

Biomarkers of agitation and aggression in Alzheimer's disease: A systematic review.

INTRODUCTION: Agitation is one of the most challenging neuropsychiatric symptoms to treat in Alzheimer's disease and has significant implications for patient and caregiver. A major source of difficulty in identifying safe and effective treatments for agitation is the lack of validated biomarkers. As such, patients may not be appropriately targeted, and biological response to pharmacotherapy cannot be adequately monitored. METHODS: This systematic review aimed to summarize evidence on the association between biomarkers and agitation/aggression in patients with Alzheimer's disease, utilizing the National Institute on Aging-Alzheimer's Association Research Framework and the Biomarkers, EndpointS, and other Tools Resource of the Food and Drug Association-National Institutes of Health Biomarker Working Group. RESULTS: This review identified six classes of biomarkers (neuropathological, neurotransmitter, neuroimaging, apolipoprotein E (APOE) genotype, inflammatory, and clusterin) associated with agitation/aggression, which were mostly diagnostic in nature. DISCUSSION: Future studies should investigate the predictive, prognostic, and monitoring capacity of biomarkers to provide insight into the longitudinal course of agitation/aggression, as well as predict and monitor biological response to a pharmacological intervention.

No differences in manic-like behaviors between voluntary ethanol and water drinking in Lateral Hypothalamic Kindled (LHK) alcohol preferring rats.

This study investigates phenotypic differences of manic-like behaviors during voluntary ethanol (vs. water) intake in alcohol preferring (P) rats, using the lateral hypothalamus kindled (LHK) rat mania model. Alcohol preferring (P) rats exhibited classic manic-like behaviors during kindling and the post-kindling intervals in all coded behaviors (p < 0.0001), lending further validity to the lateral hypothalamus kindled rat as a useful model to study mania. However, there was no significant phenotypic difference between alcohol and water drinking alcohol preferring (P) rats.

Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice.

RATIONALE: Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAA receptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments. METHODS: We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis. RESULTS: In the forced-swim assay in mice that detects antidepressant drugs, the α5ß3γ2 GABAΑ receptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5ß3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5ß3γ2 receptor antagonist, Xli-093, was not active at all. The effects of RY-080 were prevented by the non-selective benzodiazepine receptor antagonist flumazenil as well as by the selective ligands, PWZ-029 and Xli-093. These findings demonstrate that this effect of RY-080 is driven by negative allosteric modulation of α5ßγ2 GABAA receptors. RY-080 was not active in the tail-suspension test. We also demonstrated a reduction in the age-dependent hyperactivity exhibited by transgenic mice that accumulate pathological tau (rTg4510 mice) by RY-080. The decrease in hyperactivity by RY-080 was selective for the hyperactivity of the rTg4510 mice since the locomotion of control strains of mice were not significantly affected by RY-080. CONCLUSIONS: α5ßγ2 GABAA receptor NAMs might function as a pharmacological treatment for mood, amotivational syndromes, and psychomotor agitation in patients with Alzheimer's and other neurodegenerative disorders.

Peer Problems and Hyperactivity-Impulsivity Among Norwegian and American Children: The Role of 5-HTTLPR.

Peer problems are linked to attention deficit hyperactivity disorder (ADHD) symptoms and the serotonin system is thought to be involved in ADHD-related behavior. Hence, from a Gene × Environment perspective, the serotonin transporter 5-HTTLPR may play a moderating role. In two large community samples, the moderating role of 5-HTTLPR was examined related to more hyperactivity-impulsivity symptoms (HI symptoms) predicted by more peer problems. In Study 1, involving 642 Norwegian children, results indicated that for s-allele carriers only, caregiver-reported peer problems at age 4 predicted more parent-reported HI symptoms at age 6. In Study 2, similar results emerged involving 482 American children. Discussion focuses on differential sensitivity to the adverse effects of poor peer relations.

Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.

Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1.

Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder.

BACKGROUND/AIMS: Suicidal behavior (SB) in bipolar disorder (BD) is a complex multifactorial event resulting from an interaction of genetic, neurobiological and psychosocial factors. Recent studies identified new possible mechanisms, suggesting a role for sirtuins (SIRTs 1-7), a family of nicotinamide adenine dinucleotide-dependent enzymes with a multifaceted role in the central nervous system. The aims of the present study were: (1) to investigate the effects of the rs10997870 SIRT1 gene variant on SB in BD; (2) to explore the effects of the same gene variant on specific depressive symptoms at the severest episode. METHODS: One hundred and eighty DSM-IV bipolar outpatients were enrolled in a naturalistic cohort study. The rs10997870 polymorphism within the SIRT1 gene was analyzed. RESULTS: An association between the GG genotype and SB was detected (lifetime: p = 0.015). Compared to other genotypes, GG carriers presented more frequently psychomotor agitation (p = 0.009) and a higher Hamilton Depression Rating Scale total score (p = 0.014) at the severest depressive episode. SB and psychomotor agitation were found to be associated with GG carriers and G allele in a multivariate analysis as well. CONCLUSION: Our findings suggest a role of the rs10997870 SIRT1 gene variant in SB amongst BD patients and its association with specific depressive symptoms. Despite a number of limitations of this exploratory study, our results may provide new insight into the mechanisms underlying SB in BD.

Aceruloplasminemia With Psychomotor Excitement and Neurological Sign Was Improved by Minocycline (Case Report).

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin gene. Its prevalence is 1 in 2,000,000 people in Japan. This is a disorder of neurodegeneration with iron accumulation in the brain revealed by MRI. The iron overload induces oxidative stress and generation of reactive oxygen species, which triggers a cascade of pathological events that lead to neuronal death. Intravenous administration of an iron chelator, deferoxamine has been proposed as a method of inhibiting the accumulation of iron.The patient was a 46-year-old Japanese woman. She was diagnosed at the age of 33 years. Deferoxamine was administrated for 6 months but was discontinued due to adverse effects. On admission at the age of 46, psychomotor excitement was acute in onset. The extrapyramidal symptoms reflected iron deposition in the basal ganglia and substantia nigra in the midbrain. Ataxia and a wide-based gate reflected iron deposition in the dentate nuclei of the cerebellum. An antibiotic, minocycline at 150 mg/day successfully ameliorated the clinical symptoms.Minocycline, a second generation tetracycline, has a direct radical scavenging property due to its chemical structure. It has been reported that minocycline is similar to deferoxamine in its ability to chelate iron. Minocycline is also involved in preventing the upregulation of proinflammatory cytokines. The iron-chelating, antioxidant, and anti-inflammatory effects of minocycline were involved in this case.

A mild phenotype associated with a de novo microdeletion 10q23.1-q23.2: a new patient with a novel feature.

Chromosome 10q23 contains several genes, includingPTENandBMPR1A, the mutations or microdeletion of which are associated with aggressive polyposis and malignancies in children. Deletions in this chromosomal region have also been associated with heart anomalies, developmental delay and macrocephaly. Most of the cases reported involve thePTENandBMPR1Agenes, usually associated with complex and severe anomalies. We report a case of a boy with a de novo interstitial microdeletion in 10q23.1-q23.2 spanning 6.7 Mb with boundaries from 82 087 077 to 88 847 906, not includingPTENandBMPR1A Clinical features consisted of mildly dysmorphic facies, frontal telangiectasias, poor scholastic performance and hyperactivity. Furthermore, the boy presented toe anomalies, which appeared to be novel features associated with 10q23 deletion. Further observations of 10q23.1-q23.2 deletions are necessary to confirm the clinical features observed in the proband, and to show that deletion or mutations not involvingPTENandBMPR1Amay not be associated with severe neurological impairment and malformation anomalies.

Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders.

Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to "deorphanization", that is, identifying CYP20A1 functions and its roles in health and disease.

Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations.

OBJECTIVE: Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire. METHOD: Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes. RESULTS: More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD. CONCLUSION: Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems-ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects.

TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.

Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.

Citalopram for the Treatment of Agitation in Alzheimer Dementia: Genetic Influences.

OBJECTIVE: To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory. METHOD: We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures. RESULTS: Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks. DISCUSSION: Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation.