A role for TENM1 mutations in congenital general anosmia.

Congenital general anosmia (CGA) is a neurological disorder entailing a complete innate inability to sense odors. While the mechanisms underlying vertebrate olfaction have been studied in detail, there are still gaps in our understanding of the molecular genetic basis of innate olfactory disorders. Applying whole-exome sequencing to a family multiply affected with CGA, we identified three members with a rare X-linked missense mutation in the TENM1 (teneurin 1) gene (ENST00000422452:c.C4829T). In Drosophila melanogaster, TENM1 functions in synaptic-partner-matching between axons of olfactory sensory neurons and target projection neurons and is involved in synapse organization in the olfactory system. We used CRISPR-Cas9 system to generate a Tenm1 disrupted mouse model. Tenm1(-/-) and point-mutated Tenm1(A) (/A) adult mice were shown to have an altered ability to locate a buried food pellet. Tenm1(A) (/A) mice also displayed an altered ability to sense aversive odors. Results of our study, that describes a new Tenm1 mouse, agree with the hypothesis that TENM1 has a role in olfaction. However, additional studies should be done in larger CGA cohorts, to provide statistical evidence that loss-of-function mutations in TENM1 can solely cause the disease in our and other CGA cases.

Obsessive compulsive behaviour in autism--towards an autistic-obsessive compulsive syndrome?

A portion of autistic patients exhibit compulsive-like behaviours. In addition it has been suggested that serotonin plays a major role in both obsessive compulsive disorder (OCD) and autistic disorder. Other neurohumors such as endogenous opioids and oxytocin have also been implicated in the two disorders. There is also some pharmacological overlap between the two disorders, as well as some similar neuroimaging studies. These similarities and overlaps have led us to propose a putative OCD-autistic disorder, which should be studied in greater detail.

Unaltered alpha(2)-noradrenergic/imidazoline receptors in suicide victims: a postmortem brain autoradiographic analysis.

In vitro quantitative autoradiography of alpha(2)-adrenergic/imidazoline receptors, using [(125)I]iodoclonidine as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found no significant, region-dependent alterations in the density of alpha(2)-adrenergic receptors in brains of suicide victims as compared to matched controls. We also report age-dependent reductions in binding in the prefrontal cortex and hippocampus, as well as significant recent alcohol ingestion-dependent reductions in binding in the prefrontal cortex. Sex and time from death to autopsy did not affect iodoclonidine binding in our sample.

Is there sexual dimorphism in obsessive-compulsive disorder?

The present review addresses the question of sexual dimorphism in obsessive-compulsive disorder. It enumerates examples that could be interpreted to suggest the existence of such dimorphism from the fields of epidemiology, phenomenology, pharmacology, neuropsychology, neuroimaging and genetics. We conclude that data, at this point, are too scarce to warrant a firm conclusion. On the contrary it seems that there are enough indications in the literature that hint at the possibility of sexual dimorphism to stimulate further research in the field.

Orbitofrontal cortex dysfunction in obsessive-compulsive disorder? I. Alternation learning in obsessive-compulsive disorder: male-female comparisons.

BACKGROUND: We have previously reported a significant negative correlation between severity of symptoms and performance of an alternation learning task in female obsessive-compulsive disorder (OCD) patients. The present study was aimed at exploring this relationship between alternation learning and OCD symptom severity in male OCD patients. METHODS AND RESULTS: Eighteen female obsessive-compulsive disorder patients and 14 male non-depressed, drug free, OCD patients participated in the study. Measures of dorsolateral prefrontal function (Wisconsin Card Sorting Test) and orbitofrontal cortex function (object alternation learning) showed no significant differences between the sexes. The relationship between orbitofrontal cortex function and severity of OC symptoms was significantly different between the sexes (z=2.44. P=0.007). While this correlation was negative in the females it was positive in the males. CONCLUSIONS: These results may indicate sexual dimorphism in OCD.

Orbitofrontal cortex dysfunction in obsessive-compulsive disorder? II. Olfactory quality discrimination in obsessive-compulsive disorder.

BACKGROUND: Olfactory quality discrimination is a putative marker of orbitofrontal cortex function in mammals. As this portion of the cerebral cortex was repeatedly implicated in the pathophysiology of obsessive-compulsive disorder (OCD) this study was designed in an attempt to quantify this behavioural function in OCD patients. METHODS AND RESULTS: Olfactory quality discrimination was compared in OCD patients and healthy controls. Thirty two subjects participated in the study: 16 (13 women and 3 men) medication free OCD outpatients and 16 sex and age matched healthy controls. Olfactory tests consisted of determination of detection thresholds to isoamyl acetate, and a three way forced choice quality discrimination task, using isoamyl acetate, citral and eugenol as stimuli. No significant differences in sensitivity and performance of the quality discrimination task between the two groups were found. Within the OCD group the more severely affected patients (Y-BOCS>29) performed significantly better than the less severely affected (Y-BOCS<30) patients on the more difficult part of the quality discrimination task. Within this subgroup of patients the correlation between performance on the olfactory task and a previously reported alternation task tended to be negative as compared to a significantly positive correlation in the control group. CONCLUSIONS: It seems that olfactory quality discrimination may prove to be a useful noninvasive marker of prefrontal cortex function in OCD. Furthermore, the organization of functional modules within the orbitofrontal cortex, rather than a simple dysfunction, may prove to characterize OCD.

Increased olfactory sensitivity in first episode psychosis and the effect of neuroleptic treatment on olfactory sensitivity in schizophrenia.

Olfactory sensitivity to two odorants, isoamyl acetate and androstenone, was assessed in 19 male schizophrenic patients and 10 control subjects. Tests were performed during a drug-free period and 2-3 weeks after initiation of neuroleptic drug therapy. Olfactory sensitivity in schizophrenic patients was significantly impaired during the drug-free period and neuroleptic treatment further reduced olfactory sensitivity in these patients. The same olfactory tests were administered to 22 first-episode-psychosis patients, 12 first-episode-schizophrenia and 10 brief-psychotic-disorder patients, as well as to 20 age-matched control subjects. The first-episode-psychosis patients had significantly higher sensitivity to isoamyl acetate and to androstenone, but the incidence of anosmia to androstenone was not higher in the first episode patient group as compared to the control group. We conclude that olfactory dysfunction in schizophrenic patients, and possibly other forms of psychosis, is mainly due to long-term effects of commonly used neuroleptic drugs.

The suicide brain: a review of postmortem receptor/transporter binding studies.

The present review summarizes the last 15 years of research involving postmortem receptor/transporter binding studies on brains of suicide victims. It is our working hypothesis, on the basis of psychological, behavioral and epidemiological studies, that suicidal behavior is an independent unique behavioral entity with specific neurochemical characteristics. This review tries to test this hypothesis at the level of neurotransmitter receptors by using a different approach to data analysis. We suggest that this statistical approach, involving multivariate analyses, can contribute to the formulation of new hypotheses at the level of molecular biology and genetics. Such studies if undertaken in the future, would help define suicidal behavior as a psycho-neuro-pathological entity.

Alternation learning in obsessive-compulsive disorder.

The Wisconsin Card Sorting Test (WCST) and an alternation learning task were administered to 15 women with obsessive-compulsive disorder (OCD) and 15 age-, sex-, education-, and intelligence-matched healthy controls. OCD patients were significantly slower on the WCST as compared to the controls. Their performance on the alternation learning task was impaired relative to the control group, though this difference was diminished when we used education as a covariate. We found a significant positive correlation between performance on the alternation task and severity of symptoms in the OCD group. Performance of similar alternation tasks is impaired by damage to the orbitofrontal cortex in nonhuman primates. Therefore the data presented support the hypothesis of orbitofrontal cortex dysfunction in OCD.

Taste bud cell generation in the perihatching chick.

Chick taste bud primordia initially appear in late gestation on embryonic day 17 (E17), 4 days before hatching. To track DNA synthesis and subsequent taste bud cell proliferation between E17 and the second day post-hatching (H2), single 25 muCi injections of tritiated thymidine (specific activity = 72.5 Ci/mmol) were administered in ovo during E15, E16, E17 or E18. Anterior mandibular oral epithelium was processed for light microscopic autoradiography. Sections through each taste bud's center were analysed for label (> or = 6 silver grains/gemmal cell nucleus), and bud diameter. Results indicated a major part of gemmal cell DNA synthesis does not occur until after E19 irrespective of the day of thymidine injection, suggesting postmitotic or quiescent (decycled) cells assemble to form the early bud primordium (E17-19) based on local tissue interactions. All buds examined from E20-H2 contained labelled cells. The day of injection was important since 5-day survival cases after E16 injection yielded about 25% the number of labelled cells/bud as compared with equivalent survival cases following E17-18 injections. These results are discussed with respect to parallel changes in bud shape and increasing bud diameter, and cell proliferation in possible extra- and intragemmal sources of bud cells.

Olfactory sensitivity in major depressive disorder and obsessive compulsive disorder.

Olfactory sensitivity to two odorants, isoamyl acetate and androsterone, was assessed in 14 obsessive compulsive disorder (OCD) patients, nine major depressive disorder (MDD) patients, and 16 sex- and age-matched healthy controls. Tests were performed during a drug-free period, and 3 and 6 weeks after initiation of antidepressant drug therapy. No difference in olfactory sensitivity, to either odorant, was found between OCD patients and controls at any time. In MDD patients, a significant increase in the sensitivity to isoamyl acetate was observed 6 weeks after initiation of treatment, compared to controls.

Olfactory receptors: transduction, diversity, human psychophysics and genome analysis.

The emerging understanding of the molecular basis of olfactory mechanisms allows one to answer some long-standing questions regarding the complex recognition machinery involved. The ability of the olfactory system to detect chemicals at sub-nanomolar concentrations is explained by a plethora of amplification devices, including the coupling of receptors to second messenger generation through GTP-binding proteins. Specificity and selectivity may be understood in terms of a diverse repertoire of olfactory receptors of the seven-transmembrane-domain receptor superfamily, which are probably disposed on olfactory sensory neurons according to a clonal exclusion rule. Signal termination may be related to sets of biotransformation enzymes that process odorant molecules, as well as to receptor desensitization. Many of the underlying molecular components show specific expression in olfactory epithelium, with a well-orchestrated developmental sequence of emergence, possibly related to sensory neuronal function and connectivity requirements. A general model for molecular recognition in biological receptor repertoires allows a prediction of the number of olfactory receptors necessary to achieve efficient detection and sheds light on the analogy between the immune and olfactory systems. The molecular cloning and mapping of a human genomic olfactory receptor cluster on chromosome 17 provides insight into olfactory receptor diversity, polymorphism and evolution. Combined with future genotype-phenotype correlation, with particular reference to specific anosmia, as well as with computer-based molecular modelling, these studies may provide insight into the odorant specificity of olfactory receptors.

Evidence for genetic determination in human twins of olfactory thresholds for a standard odorant.

Olfactory thresholds for four odorants were determined in groups of monozygotic and dizygotic human twins. Odorants were presented in an ascending dilution series in odorless solvent, using a three-way forced choice method. For two of the tested odorants, 5 alpha-androst-16-en-3-one and isoamyl acetate, the thresholds showed a strong genetic component. This was demonstrated by respective values of 0.78 and 0.73 for the intraclass correlation difference, and of z = 3.69 and z = 2.71 in a within-pair difference analysis. The results for isoamyl acetate are novel, and suggest that genetic polymorphism in the affinity of odorant receptor proteins contributes to the (nearly normal) threshold distribution for this odorant.

Comparison of mu opioid receptors in brains of rats bred for high or low rate of self-stimulation.

Opiates and endogenous opioid peptides play an important role in reward-mediated behaviors, including self-stimulation. Two strains of rats, LC2-Hi and LC2-Lo, selectively bred for high vs. low rate of lateral hypothalamic self-stimulation, were employed in the present study. Quantitative autoradiography was performed on brains of adult male rats of each strain, using the mu opioid receptor agonist 3H-DAGO. Strain differences in receptor density were observed in the nucleus accumbens and in ventral areas of the hippocampus.

Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: effects of age and alcohol.

Quantitative autoradiographic analysis of serotonin 5-HT1A receptors in the human brain, using [3H]8-OH-DPAT as a ligand, reveals region-specific decreases in receptor labeling with age in several cortical and hippocampal regions and in the raphe nuclei. This is due to a change in receptor density (Bmax) with no apparent change in affinity (Kd) as affirmed by saturation binding analysis on representative cortical regions. The presence of alcohol is associated with decreased binding in several cortical gyri. Suicide, gender and postmortem delay had no effect on 8-OH-DPAT binding.

Fetal human brain exhibits a prenatal peak in the density of serotonin 5-HT1A receptors.

High densities of serotonergic 5-HT1A receptors, in excess of adult levels, were found in the human fetal brain between the 16th and 22nd weeks of gestation, 5-HT1A receptors were measured by quantitative autoradiography using brain sections of fetuses aborted at gestational ages 16-22 weeks. The highest receptor concentrations were detected in the cortex and hippocampus. Two brains obtained from fetuses with Down's syndrome at 22 and 24 weeks gestation exhibited abnormal receptor levels compared to age matched controls. The presence of an early, prenatal peak of 5-HT1A receptors in fetal cortex and hippocampus suggests that these receptors play a role in human brain development and may also be involved in developmental disorders such as Down's syndrome.

Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide.

In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measured by autoradiography.

Regionally selective increases in mu opioid receptor density in the brains of suicide victims.

The effect of ageing and suicide on mu opioid receptors was studied in the human brain postmortem. Quantitative autoradiography with [3H]DAGO revealed region specific increases in mu receptor density with age. Suicide was accompanied by a significant increase, up to 9-fold, in mu receptor density in the young, but not the old, subjects as compared to age-matched controls. This effect was evident in the frontal and temporal cortical gyri. Saturation binding studies with the same ligand show that the increased binding in the elderly and in the young suicides is due to an increase in receptor density (Bmax) rather than affinity (Kd).

Autoradiographic analysis of age-dependent changes in serotonin 5-HT2 receptors of the human brain postmortem.

Autoradiographic analysis of 5-HT2 receptors in the human brain, using [3H]ketanserin as a ligand, reveals region-specific changes in receptor labeling as a function of age. In the prefrontal cortex and hippocampal dentate gyrus of 12 normal subjects, label density decreases sharply with age over the 2nd and 3rd decades, reaches a minimum around age 50 and then starts to increase again in the 6th and 7th decades. Other brain regions studied, including frontoparietal and temporal cortex, basal ganglia and thalamus, did not show significant changes with age. Saturation binding experiments on prefrontal cortical samples from 23 normal subjects reveal that the decrease in label density is due to changes in receptor density (Bmax) with no apparent change in affinity (Kd). Sex, presence of alcohol and postmortem delay had no effect on ketanserin binding.