A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF Met/Met ) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF Met was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.Depression and anxiety disorders have genetic predispositions, yet the particular genes that contribute to this pathology are not known. One candidate gene is BDNF, because of its established roles in neuronal survival, differentiation, and synaptic plasticity. The recent discovery of a single-nucleotide polymorphism (SNP) in the bdnf gene (Val66Met), found only in humans, leading to a Met substitution for Val at codon 66 in the prodomain, has provided a valuable tool to assess potential contributions of BDNF to affective disorders. This polymorphism is common in human populations with an allele frequency of 20 to 30% in Caucasian populations (1). This alteration in a neurotrophin gene correlates with reproducible alterations in human carriers. Humans heterozygous for the Met allele have smaller hippocampal volumes (2-4) and perform poorly on hippocampal-dependent memory tasks (5,6). However, in genetic association studies for depression and anxiety disorders, there is little consensus as to whether this allele confers susceptibility.The mechanisms that contribute to altered BDNF Met function have been studied in neuronal culture systems. The distribution of BDNF Met to neuronal dendrites and its activity-dependent secretion are decreased (6-8). These trafficking abnormalities are likely to reflect impaired binding of BDNF Met to a sorting protein, sortilin, which interacts with BDNF in the prodomain †To whom correspondence should be addressed.

Brain serotonin (5-HT) has been implicated in a number of physiological processes and pathological conditions. These effects are mediated by at least 14 different 5-HT receptors. We have inactivated the gene encoding the 5-HT 1A receptor in mice and found that receptor-deficient animals have an increased tendency to avoid a novel and fearful environment and to escape a stressful situation, behaviors consistent with an increased anxiety and stress response. Based on the role of the 5-HT 1A receptor in the feedback regulation of the 5-HT system, we hypothesize that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals. This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans.Brain serotonin (5-HT) is implicated in the control of a wide variety of physiological processes such as nociception, cardiovascular function, and thermoregulation, as well as in different behavioral processes including feeding, aggression, and response to stress (reviewed in refs. 1-5). The 5-HT system also appears to be involved in the etiology of neuropsychiatric disorders such as depression and anxiety (reviewed in refs. 6 and 7). In recent years, our understanding of the physiological and pathological aspects of the 5-HT system has benefited from the identification, classification, and more recently the cloning of the 5-HT receptor subtypes (8). Among the receptor subtypes that have received the most attention is the 5-HT 1A receptor (5-HT 1A R). This was because of the availability of 5-HT 1A R agonists and the implication of the 5-HT 1A receptor in anxiety (6, 9).The 5-HT 1A R, like most of the 5-HT receptors, belongs to the superfamily of G-protein coupled receptors (10, 11). It is negatively coupled to adenyl cyclase. Brain 5-HT 1A R is located both pre-and postsynaptically. Presynaptic 5-HT 1A R is found mainly in the dorsal and median raphe nuclei. Activation of these receptors by agonists causes a reduction in the firing rate of serotonergic neurons (12-14) and leads to the suppression of 5-HT synthesis, 5-HT turnover, and 5-HT release in the diverse projection areas (15, 16). Postsynaptic 5-HT 1A R is found in limbic regions (such as hippocampus and septum) and in some cortical layers. As in the case of presynaptic receptors, activation of postsynaptic 5-HT 1A R is generally believed to induce a decrease in the firing rate of the postsynaptic cell (14).The 5-HT 1A R has been extensively studied by pharmacological methods. Activation of the receptor by agonists results in an anxiolytic effect (17, 18). Correlations were found among the time and dose dependency of the anxiolytic effect, the inhibition of serotonergic firing in the dorsal raphe nuclei, and the inhibition of 5-HT release after systemic administration of agonists (19,20). The 5-HT 1A R partial agonist buspirone and a series of congeners also produce this neurochemical effect and are used clinically for...

The prefrontal cortex plays a key role in the control of higher brain functions and is involved in the pathophysiology and treatment of schizophrenia. Here we report that approximately 60% of the neurons in rat and mouse prefrontal cortex express 5-HT(1A) and/or 5-HT2A receptor mRNAs, which are highly co-localized (approximately 80%). The electrical stimulation of the dorsal and median raphe nuclei elicited 5-HT1A-mediated inhibitions and 5-HT2A-mediated excitations in identified pyramidal neurons recorded extracellularly in rat medial prefrontal cortex (mPFC). Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons. Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists. This inhibitory effect was antagonized by WAY-100635 and the prior inactivation of 5-HT1A receptors in rats and was absent in mice lacking 5-HT1A receptors. These observations help to clarify the interactions between the mPFC and the raphe nuclei, two key areas in psychiatric illnesses and improve our understanding of the action of atypical antipsychotics, acting through these 5-HT receptors.

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Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, "top-down" influences on risk assessment.

MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-II alcoholism and in cigarette smokers. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin 1A receptors (5-HT1A receptors). Because chronic stress selectively down-regulates the 5-HT 1A receptors in the hippocampus, we hypothesized that mice lacking these receptors may exhibit abnormalities reminiscent of symptoms of stress-related psychiatric disorders. In particular, a hippocampal deficit in the 5-HT1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT 1A receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT1A-knockout (KO) mice. 5-HT1A-KO animals showed a deficit in hippocampal-dependent learning and memory tests, such as the hidden platform (spatial) version of the Morris water maze and the delayed version of the Y maze. The performance of KO mice was not impaired in nonhippocampal memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory. Furthermore, paired-pulse facilitation in the dentate gyrus of the hippocampus was impaired in 5-HT 1A-KO mice. Finally, 5-HT1A-KO mice, as compared with wild-type animals, displayed higher limbic excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration. These results demonstrate that 5-HT1A receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT 1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders.A deficiency of postsynaptic serotonin 1A (5-HT 1A ) has been implicated in mood disorders, such as depression and posttraumatic stress disorder and panic disorder (1-4). In particular, a receptor deficiency has been reproducibly found in the limbic systems of people with mood disorders (3, 5). Decreased 5-HT1A receptor binding was found in the brains of depressed suicide victims (6), and recent brain-imaging studies performed with positron-emission tomography have revealed decreased 5-HT 1A -receptor densities in the medial temporal lobe and other limbic brain regions of patients with major depression (7,8). Also, chronic stress, which is well known to be a major factor in the development of mood disorders, has been shown to lead to a specific down-regulation of 5-HT 1A receptors in the hippocampus of experimental animals (9-15). These results strongly suggest that down-regulation of 5-HT 1A receptors, caused by either genetic or stress-related processes, may significantly contribute to the development of mood disorders in humans. Specifically, a hippocampal deficit in 5-HT 1A receptors could contribute to the cognitive abnormalities often seen in people with mood disorders (16-19).The serotonergic system seems to play a role in behaviors that invo...

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