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Neuropsin and TAAR1: Dark Horses of Anxiety

15 June 2011. Two recent studies turn up new clues for the regulation of anxiety in some obscure places. One study, published in Nature on 19 May 2011, identifies an extracellular matrix protease called neuropsin as a key player in converting stressful events into anxious behavior in mice. Led by Robert Pawlak of the University of Leicester, U.K., this study outlines a path in which stress spurs neuropsin to cleave EphB2 receptors on amygdala neurons, which then triggers a cascade of events involving NMDA receptors and Fkbp5 gene transcription. The second study, published in PNAS on 17 May 2011, explores the somewhat mysterious trace amine-associated receptor 1 (TAAR1). A team led by Marius Hoener of F. Hoffmann-La Roche in Basel, Switzerland, reports the discovery of a selective agonist for TAAR1, which not only has anxiolytic effects in mice, but also mimics antipsychotic drugs in various hyperlocomotion tests used for screening drugs for schizophrenia.

Both studies offer a glimpse into the multiple and complicated mechanisms behind anxiety, which is a common comorbidity for people with schizophrenia, and touch on other clues related to the disorder. The first study centers on how neuropsin cleaves EphB2, a receptor tyrosine kinase that associates with NMDA receptors, whose function may be compromised in schizophrenia (see SRF hypothesis). Other threads of evidence link a ligand for EphB2, called ephrin B2, to schizophrenia, including a genetic association study (see SZGene entry), and a recent report identifying ephrin B2 as participating in the control of neuronal migration during development via the reelin (see SZGene entry) pathway (Sentürk et al., 2011).

The second study explores the selective activation of TAAR1, a receptor for trace amines. Trace amines are byproducts of amino acid production and are found in the brain at levels so low as to seem irrelevant. But trace amines garnered more respect in 2001, when researchers discovered a family of receptors for them, including TAAR1 (Borowsky et al., 2001), which localizes to dopamine and serotonin-containing neurons in the brain. Abnormal levels of trace amines have been reported for schizophrenia and other disorders, and have been proposed to play a role in regulating dopamine and serotonin systems (Burchett and Hicks, 2006).

Stressful steps to anxiety
To explore the possibility of stress-related signaling at the extracellular matrix-neuron interface, first author Benjamin Attwood and his colleagues in Leicester began with a demonstration that neuropsin selectively cleaves the extracellular portion of EphB2 in cultured cells. To address whether this cleavage was impacted by emotional "stress," the researchers restrained the mice, which activates the amygdala, and measured a 50 percent increase in neuropsin levels, and a twofold increase in EphB2 receptors in the neuronal membranes afterwards. Co-immunoprecipitation studies indicated that cleaved EphB2 receptors dissociated from the NR1 subunit of the NMDA receptors, with which they normally cluster. This dissociation did not transpire in knockout mice lacking neuropsin, but it could be rescued by injecting the amygdala of these animals with neuropsin.

The researchers also found that this neuropsin-dependent EphB2 cleavage boosted transcription of Fkbp5, a gene whose activation is implicated in turning stressful events into post-traumatic stress disorder (Segman et al., 2005). When stressed, mice lacking neuropsin had a smaller induction of Fkbp5 and less anxiety than wild-type animals, as measured by entries into open arms of an elevated-plus maze. These unflappable mice could be turned into apprehensive ones by injecting neuropsin into their amygdalae before stressing them. Other manipulations supported a role for other steps in the neuropsin pathway: wild-type mice displayed less anxious behavior after an episode of stress when EphB2 receptors were blocked with an antibody, or when Fkbp5 gene expression was decreased in the amygdala.

A new TAAR1-get
TAAR1 is a G protein-coupled receptor residing in the dopamine and serotonin-containing cells of the brain and, like other amine receptors, it activates cAMP production inside the cell. TAAR1 knockout mice are hypersensitive to amphetamine, showing elevated locomotion and increased release of dopamine, serotonin, and noradrenaline relative to wild-type mice (Wolinsky et al., 2007). This suggests that TAAR1 normally keeps monoaminergic signaling in check.

But studying the consequences of TAAR1 activation directly with any precision has been stymied by the lack of a selective agonist. This is where first author Florent Revel of Hoffmann-La Roche and colleagues step in, with an introduction to and characterization of a new selective TAAR1 agonist, called RO166017. This agonist had high affinity for and potency at mouse, rat, monkey, and human versions of TAAR1, spurring cAMP production to levels similar to those reached by endogenous trace amines. Testing for binding to 123 other proteins found that the agonist preferred to bind to TAAR1 in every case, usually with a greater than 100-fold selectivity, making the compound a clean way to activate the TAAR1 receptor.

In mouse brain slices, the agonist clearly modulated the firing rates of other aminergic neurons. It decreased the firing rates of dopamine neurons in the ventral tegmental area (VTA) and of serotonin neurons in the dorsal raphe nucleus (DRN), but not in the locus ceruleus (LC), which is devoid of TAAR1 receptors. Importantly, RO166017-induced responses weren't apparent in knockout animals lacking the TAAR1 receptor, and they were blocked by a TAAR1 antagonist, called EPPTB, in wild-type mice—which both support the selectivity of the agonist's action.

Behaviorally, the RO166017 agonist had anxiolytic and antipsychotic-like effects in mice. When given orally, the agonist prevented stress-induced hyperthermia in wild-type mice in a dose-dependent manner, but not in TAAR1 knockouts. The agonist also inhibited the hyperlocomotion induced by cocaine in wild-type mice (but not in TAAR1 knockouts), achieving a level of inhibition similar to the antipsychotic olanzapine. In a more specific test, the agonist stemmed the hyperlocomotion due to elevated levels of synaptic dopamine that occur in mice lacking the dopamine transporter (DAT) that pumps dopamine back into the neuron. The agonist could also temper hyperlocomotion triggered by inhibition of the NMDA receptor—a model for schizophrenia.

These results put TAAR1 forward as an alternative route to modulating monoaminergic systems in the brain—one that might have fewer side effects than the direct modifications to these systems made by current antipsychotic drugs. Together, the two studies provide a reminder that there is still a lot to learn about the mechanisms behind anxiety—a situation that can lead to new and unexpected therapeutic targets.—Michele Solis.

References:
Attwood BK, Bourgognon JM, Patel S, Mucha M, Schiavon E, Skrzypiec AE, Young KW, Shiosaka S, Korostynski M, Piechota M, Przewlocki R, Pawlak R. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature. 2011 May 19;473: 372-5. Abstract

Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011 May 17;108: 8485-90. Abstract

Comments on Related News


Related News: A Tale of Two City Exposures and the Brain

Comment by:  John McGrath, SRF Advisor
Submitted 22 June 2011
Posted 22 June 2011

The findings from Lederbogen et al. are very thought provoking. The dissociation between the fMRI correlates of current versus early life urbanicity is unexpected. The authors have replicated their finding in an independent sample, reducing the chance that the finding was a type 1 error.

It is heartening to see important clues from epidemiology influencing fMRI research design. With respect to schizophrenia, the findings provide much-needed clues to the neurobiological correlates of urban birth (Pedersen and Mortensen, 2001; Pedersen and Mortensen, 2006; Pedersen and Mortensen, 2006). Somewhat to the embarrassment of the epidemiology research community, the link between urban birth and risk of schizophrenia has been an area of research where the strength of the empirical evidence has been much stronger than hypotheses proposed to explain the findings (McGrath and Scott, 2006; March et al., 2008). The new findings should trigger more focused research exploring the fMRI correlates in urban- versus rural-born individuals with schizophrenia.

References:

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and place. Epidemiol Rev . 2008 Jan 1 ; 30():84-100. Abstract

McGrath J, Scott J. Urban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses. Epidemiol Psichiatr Soc . 2006 Oct-Dec ; 15(4):243-6. Abstract

Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry . 2001 Nov 1 ; 58(11):1039-46. Abstract

Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol . 2006 Jun 1 ; 163(11):971-8. Abstract

Pedersen CB, Mortensen PB. Urbanization and traffic related exposures as risk factors for schizophrenia. BMC Psychiatry . 2006 Jan 1 ; 6():2. Abstract

View all comments by John McGrath

Related News: A Tale of Two City Exposures and the Brain

Comment by:  Elizabeth Cantor-Graae
Submitted 23 June 2011
Posted 23 June 2011

The study by Lederbogen et al. linking neural processes to epidemiology opens up an exciting avenue of inquiry, It suggests that exposure to urban upbringing could modify brain activity. Whether that could lead to schizophrenia per se remains to be seen.

Still, one might want to keep in mind that there is no evidence that urban-rural differences in schizophrenia risk are causally related to individual exposure. Pedersen and Mortensen (2006) showed that the association between urban upbringing and the development of schizophrenia is attributable both to familial-level factors as well as individual-level factors. Thus, the link between urbanicity and schizophrenia may be mediated by genetic factors, and if so, the social stressors shown by Lederbogen may in turn be related to those same genes.

Although it might be tempting to speculate whether Lederbogen’s findings have implications for migrant research, the “migrant effect” does not seem neatly explained by urban birth/upbringing. To the contrary, our findings show that the dose-response relationship between urbanization and schizophrenia (Pedersen and Mortensen, 2001) could be replicated only among persons born in Denmark whose parents had both been born in Denmark, and not in second-generation immigrants (Cantor-Graae and Pederson, 2007). Second-generation immigrants had an increased risk of developing schizophrenia independently of urban birth/upbringing (Cantor-Graae and Pedersen, 2007).

References:

Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol. 2006; 163:971-8. Abstract

Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry. 2001; 58:1039-46. Abstract

Cantor-Graae E, Pedersen CB. Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychol Med. 2007; 37:485-94. Abstract

View all comments by Elizabeth Cantor-Graae

Related News: A Tale of Two City Exposures and the Brain

Comment by:  James Kirkbride
Submitted 27 June 2011
Posted 27 June 2011

Mannheim, Germany, has long played a pivotal role in unearthing links between the environment and schizophrenia (Hafner et al., 1969). Using administrative incidence data from Mannheim in 1965, Hafner and colleagues were amongst the first groups to independently verify Faris and Dunham’s seminal work from Chicago in the 1920s, which showed that hospitalized admission rates of schizophrenia were higher in progressively more urban areas of the city (Faris and Dunham, 1939). Now, almost 50 years later, Mannheim’s historical pedigree in this area looks set to endure, following the publication of the landmark study by Lederbogen et al. in Nature, which reported for the first time associations of urban living and upbringing with increased brain activity amongst healthy volunteers in two brain regions involved in determining environmental threat and processing stress responses.

Tantalizingly, their work bridges epidemiology and neuroscience, and provides some of the first empirical data to directly implicate functional neural alterations in stress processing associated with living in urban environments. One important step will now be to discover whether such neural changes (following exposure to urban environments) are associated with clinical phenotypes, such as schizophrenia. This would support long-speculated paradigms of social stress (Selten and Cantor-Graae, 2005) as an important mechanism in a causal pathway between the environment and psychosis, although alternative environmental exposures in urban areas, including viral hypotheses and vitamin D, should not yet be excluded.

The work by Lederbogen et al. opens many avenues for possible study, including replication of their findings in clinical samples (via case-control designs) and using population-based rather than convenience samples. One of the greatest challenges in the social epidemiology of psychiatric disorders is to identify the specific suite of factors that underpin associations between the urban environment and the risk of clinical disorder. While Lederbogen et al. did not provide specific enlightenment on what these factors might be, their work also informs this search, because it suggests that focusing on factors likely to induce (or protect against) social stress would be potentially fruitful. To this end, their work should pave the way for mimetic studies, in both non-clinical and clinical populations, to investigate neural processing in relation to candidate social risk factors for psychiatric illness that were implicated in previous epidemiological studies (Cantor-Graae and Selten, 2005; March et al., 2008). These candidates may include migration or minority group membership (Coid et al., 2008), childhood traumas and other major life events (Kendler et al., 1992; Morgan et al., 2007), neighborhood socioeconomic deprivation (Croudace et al., 2000), income inequality (Boydell et al., 2004), and both individual-level social networks and neighborhood-level social cohesion and ethnic density (Kirkbride et al., 2008); some of these factors may also mitigate the effects of social stress.

The interface between social epidemiology and social neuroscience will also potentially provide new avenues by which to develop public health interventions. Presently, universal prevention strategies that focus on community-based interventions to prevent mental illness are not readily viable (Kirkbride et al., 2010), given both the absolute rarity of psychotic disorder and the relative ubiquity of broadly defined exposures such as urban living (many people live in urban environments, but only a handful of them will ever develop a psychotic illness). However, social neuroscience breakthroughs like those reported here may increase the viability of community-based public health initiatives by making it possible to move the focus of the intervention from preventing the clinical phenotype to preventing the abnormal neural changes associated with social-stress processing. Importantly, such strategies must also consider the possible benefits of enhanced social-stress processing in urban environments, which might be an important adaptation to more threatening environments. Because social stress may be associated with a range of neuropsychiatric and somatic disorders, public health strategies that target reductions in social stress rather than any single disorder may lead to significant improvements in population health across a range of morbidities. Such strategies, if justifiable, may also be cost effective, since a single intervention may prevent a range of disorders.

References:

Hafner H, Reimann H, Immich H, Martini H. Inzidenz seelischer Erkrankungen in Mannheim 1965. Soc Psychiatr. 1969;4:127-35.

Faris REL, Dunham HW. Mental disorders in urban areas. Chicago: University of Chicago Press; 1939.

Selten JP, Cantor-Graae E. Social defeat: risk factor for schizophrenia? Br J Psychiatry. 2005 August 1;187(2):101-2. Abstract

Cantor-Graae E, Selten J-P. Schizophrenia and Migration: A Meta-Analysis and Review. Am J Psychiatry. 2005 January 1;162(1):12-24. Abstract

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and Place. Epidemiol Rev. 2008;30:84-100. Abstract

Coid JW, Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M, Jones PB. Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study. Arch Gen Psychiatry. 2008;65(11):1250-8. Abstract

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry. 1992 Feb;49(2):109-16. Abstract

Morgan C, Kirkbride JB, Leff J, Craig T, Hutchinson G, McKenzie K, Morgan K, Dazzan P, Doody GA, Jones P, Murray R, Fearon P. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med. 2007;37(4):495-503. Abstract

Croudace TJ, Kayne R, Jones PB, Harrison GL. Non-linear relationship between an index of social deprivation, psychiatric admission prevalence and the incidence of psychosis. Psychol Med. 2000 Jan;30(1):177-85. Abstract

Boydell J, van Os J, McKenzie K, Murray RM. The association of inequality with the incidence of schizophrenia--an ecological study. Soc Psychiatry Psychiatr Epidemiol. 2004 Aug;39(8):597-9. Abstract

Kirkbride J, Boydell J, Ploubidis G, Morgan C, Dazzan P, McKenzie K, Murray RM, Jones PB. Testing the association between the incidence of schizophrenia and social capital in an urban area. Psychol Med. 2008;38(8):1083-94. Abstract

Kirkbride JB, Coid JW, Morgan C, Fearon P, Dazzan P, Yang M, Lloyd T, Harrison GL, Murray RM, Jones PB. Translating the epidemiology of psychosis into public mental health: evidence, challenges and future prospects. J Public Ment Health. 2010;9(2):4-14. Abstract

View all comments by James Kirkbride

Related News: A Tale of Two City Exposures and the Brain

Comment by:  Wim Veling
Submitted 5 July 2011
Posted 5 July 2011

This publication is interesting and important, as it is one of the first efforts to connect epidemiological findings to neuroscience. Both fields of research have made great progress over the last decades, but results were limited because epidemiologists and neuroscientists rarely joined forces.

Several risk factors that implicate preconceptional, prenatal, or early childhood exposures have been consistently related to schizophrenia in epidemiological studies, including paternal age at conception, early prenatal famine, urban birth, childhood trauma, and migration (Van Os et al., 2010). While some of these associations are likely to be causal, the mechanisms by which they are linked to schizophrenia are still largely unknown. A next phase of studies is required, the methods and measures of which link social environment to psychosis, brain function, and genes. The study by Lederbogen and colleagues is a fine example of such an innovative research design. Their findings are consistent with hypotheses of social stress mediating the relationship between environmental factors and schizophrenia. It stimulates further research in this direction.

Two key issues need to be addressed. First, measures of social pathways should be refined (March et al., 2008). Which aspects of the daily social environment contribute to the onset of psychotic symptoms, how do these symptoms develop, and which individual characteristics moderate this outcome? It is extremely difficult to investigate daily social environments, because they are highly complex, cannot be controlled, are never exactly the same, and are strongly influenced by the individual’s behavior. Arguably, the only way to test mechanisms of psychotic responses to the social environment, and the moderators thereof, is to randomize individuals to controlled experimental social risk environments. Virtual reality (VR) technology, that is, substituting sense data from the natural world with sense data about an imaginary world that change in response to the user’s actions in an interactive three-dimensional virtual world, offers the possibility to do so. Freeman pioneered VR in psychosis research, investigating safety and feasibility (Fornells-Ambrojo et al., 2008; Freeman, 2008); however, there are no studies investigating mechanisms of risk environments. Our group recently found in a small pilot study that virtual environments with high population density or low ethnic density appear to elicit more physiological and subjective stress, as well as higher level of paranoia towards avatars (Brinkman et al., 2011). Larger studies and more experiments are needed.

Second, how are early social experiences translated to brain dysfunction? Another recent development has been in the field of epigenetics. Epigenetic mechanisms may mediate the effects of environmental risk factors, as the epigenetic status of the genome can be modified in response to the environment during embryonic growth, and probably also in the early years of life (Heijmans et al., 2009). Preliminary evidence suggests that epigenetic differences may be related to schizophrenia (Mill et al., 2008), but these epigenetic studies have not yet included environmental exposures. Epidemiologic studies may be a tool to detect epigenetic mechanisms in schizophrenia. Environmental exposures such as prenatal famine or migration may be used, as these exposures have been related to schizophrenia, can be measured with sufficient precision, offer homogeneously exposed populations for study, and had plausible biological pathways suggested for them (Veling et al. Environmental studies as a tool for detecting epigenetic mechanisms in schizophrenia. In: Petronis A, Mill J, editors. Epigenetics and Human Health: Brain, Behavior and Epigenetics. Heidelberg: Springer; 2011). Comparing the epigenome of exposed and unexposed schizophrenia cases and controls may help us to understand how gene expression affects disease risk.

As far fetched and futuristic as these research designs perhaps may seem, the publication of Lederbogen and colleagues shows that novel approaches can be very fruitful. If we improve interdisciplinary collaboration and use new technology, we may advance from associations to understanding in etiologic schizophrenia research.

References:

Van Os J, Kenis G, Rutten BPF. The environment and schizophrenia. Nature. 2010;468:203-12. Abstract

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, et al. Psychosis and place. Epidemiological Reviews. 2008;30:84-100. Abstract

Fornells-Ambrojo M, Barker C, Swapp D, Slater M, Antley A, Freeman D. Virtual Reality and persecutory delusions: safety and feasibility. Schizophrenia Research. 2008;104:228-36. Abstract

Freeman D. Studying and treating schizophrenia using Virtual Reality: a new paradigm. Schizophrenia Bulletin. 2008;34:605-10. Abstract

Brinkman WP, Veling W, Dorrestijn E, Sandino G, Vakili V, Van der Gaag M. Virtual reality to study responses to social environmental stressors in individuals with and without psychosis. Studies in Health Technology and Informatics. 2011;167:86-91. Abstract

Heijmans BT, Tobi EW, Lumey LH, Slagboom PE. The epigenome; archive of the prenatal environment. Epigenetics. 2009;4:526-31. Abstract

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. American Journal of Human Genetics. 2008;82:696-711. Abstract

Veling W, Lumey LH, Heijmans BT, Susser E. Environmental studies as a tool for detecting epigenetic mechanisms in schizophrenia. In: Petronis A, Mill J, editors. Epigenetics and Human Health: Brain, Behavior and Epigenetics. Heidelberg: Springer; 2011.

View all comments by Wim Veling

Related News: A Tale of Two City Exposures and the Brain

Comment by:  Dana March
Submitted 7 July 2011
Posted 7 July 2011

The paper by Lederbogen and colleagues represents a critical step in elucidating the mechanisms underlying the consistent association between urban upbringing and adult schizophrenia. As John McGrath rightly points out, the urbanicity findings have long been in search of hypotheses. We understand little about what the effects of place on psychosis might actually be (March et al., 2008). What it is about place that matters for neurodevelopment and for schizophrenia in particular can be greatly enriched by a translational approach linking epidemiological findings to clinical and experimental science (Weissman et al., 2011), which will in turn help us formulate and refine our hypotheses about why place matters. Lederbogen and colleagues have opened the door in Mannheim. Where we go from here will require creativity, persistence, and collaboration.

References:

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and place. Epidemiol Rev . 2008 Jan 1 ; 30:84-100. Abstract

Weissman MM, Brown AS, Talati A. Translational epidemiology in psychiatry: linking population to clinical and basic sciences. Arch Gen Psychiatry . 2011 Jun 1 ; 68(6):600-8. Abstract

View all comments by Dana March