Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression

Decreased serotonergic activity has been implicated in anxiety and major depression, and antidepressants directly or indirectly increase the long-term activity of the serotonin system. A key component of serotonin circuitry is the 5-HT1A autoreceptor, which functions as the major somatodendritic autoreceptor to negatively regulate the “gain” of the serotonin system. In addition, 5-HT1A heteroreceptors are abundantly expressed post-synaptically in the prefrontal cortex (PFC), amygdala, and hippocampus to mediate serotonin actions on fear, anxiety, stress, and cognition. Importantly, in the PFC 5-HT1A heteroreceptors are expressed on at least two antagonist neuronal populations: excitatory pyramidal neurons and inhibitory interneurons. Rodent models implicate the 5-HT1A receptor in anxiety- and depression-like phenotypes with distinct roles for pre- and post-synaptic 5-HT1A receptors. In this review, we present a model of serotonin-PFC circuitry that integrates evidence from mouse genetic models of anxiety and depression involving knockout, suppression, over-expression, or mutation of genes of the serotonin system including 5-HT1A receptors. The model postulates that behavioral phenotype shifts as serotonin activity increases from none (depressed/aggressive not anxious) to low (anxious/depressed) to high (anxious, not depressed). We identify a set of conserved transcription factors including Deaf1, Freud-1/CC2D1A, Freud-2/CC2D1B and glucocorticoid receptors that may confer deleterious regional changes in 5-HT1A receptors in depression, and how future treatments could target these mechanisms. Further studies to specifically test the roles and regulation of pyramidal vs. interneuronal populations of 5-HT receptors are needed better understand the role of serotonin in anxiety and depression and to devise more effective targeted therapeutic approaches.

[1]  K. Krishnan,et al.  Prominent Reduction in Pyramidal Neurons Density in the Orbitofrontal Cortex of Elderly Depressed Patients , 2005, Biological Psychiatry.

[2]  R. Veh,et al.  Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors. , 2004, Brain research. Molecular brain research.

[3]  M. Joëls,et al.  Chronic unpredictable stress causes attenuation of serotonin responses in cornu ammonis 1 pyramidal neurons , 2003, Neuroscience.

[4]  Javier DeFelipe,et al.  Pyramidal cell axons show a local specialization for GABA and 5‐HT inputs in monkey and human cerebral cortex , 2001, The Journal of comparative neurology.

[5]  P. Celada,et al.  The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. , 2004, Journal of psychiatry & neuroscience : JPN.

[6]  J. Crawley,et al.  Behavioral Phenotyping Strategies for Mutant Mice , 2008, Neuron.

[7]  P. Gorwood,et al.  Generalized anxiety disorder and major depressive disorder comorbidity: an example of genetic pleiotropy? , 2004, European Psychiatry.

[8]  Jordi Serrats,et al.  Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. , 2004, Cerebral cortex.

[9]  N. Kushwaha,et al.  Heterodimerization of Mineralocorticoid and Glucocorticoid Receptors at a Novel Negative Response Element of the 5-HT1A Receptor Gene* , 2001, The Journal of Biological Chemistry.

[10]  M. Stryker,et al.  Cortical Degeneration in the Absence of Neurotrophin Signaling Dendritic Retraction and Neuronal Loss after Removal of the Receptor TrkB , 2000, Neuron.

[11]  E. Lambe,et al.  Layer II/III of the Prefrontal Cortex: Inhibition by the Serotonin 5-HT1A Receptor in Development and Stress , 2009, The Journal of Neuroscience.

[12]  L. Lanfumey,et al.  Corticosteroid–serotonin interactions in the neurobiological mechanisms of stress-related disorders , 2008, Neuroscience & Biobehavioral Reviews.

[13]  K. Lesch,et al.  Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour , 2012, Philosophical Transactions of the Royal Society B: Biological Sciences.

[14]  Z. Borhegyi,et al.  Fast Synaptic Subcortical Control of Hippocampal Circuits , 2009, Science.

[15]  Wolfgang Wadsak,et al.  Reduced Serotonin-1A Receptor Binding in Social Anxiety Disorder , 2007, Biological Psychiatry.

[16]  Edwin J. Weeber,et al.  Pet-1 ETS Gene Plays a Critical Role in 5-HT Neuron Development and Is Required for Normal Anxiety-like and Aggressive Behavior , 2003, Neuron.

[17]  M. Toth Transcriptional regulation of the 5-HT2A receptor , 1995, Behavioural Brain Research.

[18]  Rupert Lanzenberger,et al.  The Serotonin-1A Receptor in Anxiety Disorders , 2009, Biological Psychiatry.

[19]  Rupert Lanzenberger,et al.  Cortisol plasma levels in social anxiety disorder patients correlate with serotonin-1A receptor binding in limbic brain regions. , 2010, The international journal of neuropsychopharmacology.

[20]  R Hen,et al.  Enhanced aggressive behavior in mice lacking 5-HT1B receptor. , 1994, Science.

[21]  Abbas F. Sadikot,et al.  Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action , 2007, Neuron.

[22]  Zoe R. Donaldson,et al.  Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior , 2014, Neuropsychopharmacology.

[23]  Benjamin D. Sachs,et al.  Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice , 2012, Molecular Psychiatry.

[24]  K. Ressler,et al.  Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic , 2007, Nature Neuroscience.

[25]  K. Shedden,et al.  The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. , 2011, Archives of general psychiatry.

[26]  J. Mann,et al.  The serotonergic system in mood disorders and suicidal behaviour , 2013, Philosophical Transactions of the Royal Society B: Biological Sciences.

[27]  G. Rajkowska,et al.  GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression , 2007, Neuropsychopharmacology.

[28]  Meng Zhang,et al.  ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation , 2010, Proceedings of the National Academy of Sciences.

[29]  Dennis S. Charney,et al.  Ketamine for Depression: Where Do We Go from Here? , 2012, Biological Psychiatry.

[30]  H. V. Van Tol,et al.  Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene. , 1990, The Journal of biological chemistry.

[31]  D. David,et al.  Functional Status of Somatodendritic Serotonin 1A Autoreceptor after Long-Term Treatment with Fluoxetine in a Mouse Model of Anxiety/Depression Based on Repeated Corticosterone Administration , 2012, Molecular Pharmacology.

[32]  R. Porsolt,et al.  Depression: a new animal model sensitive to antidepressant treatments , 1977, Nature.

[33]  A. Charest,et al.  Cloning and differentiation-induced expression of a murine serotonin1A receptor in a septal cell line , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[34]  Michael Bader,et al.  Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform , 2003, Science.

[35]  N. Alenina,et al.  Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin , 2012, Translational Psychiatry.

[36]  Jun Li,et al.  [Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children]. , 2002, Zhonghua yi xue za zhi.

[37]  Gustavo Turecki,et al.  Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide , 2003, The Journal of Neuroscience.

[38]  Marco Leyton,et al.  The role of serotonin in human mood and social interaction Insight from altered tryptophan levels , 2002, Pharmacology Biochemistry and Behavior.

[39]  S. Henriksen,et al.  5-HT7 Receptor Inhibition and Inactivation Induce Antidepressantlike Behavior and Sleep Pattern , 2005, Biological Psychiatry.

[40]  R Hen,et al.  Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  G. Rajkowska,et al.  Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder. , 2009, The international journal of neuropsychopharmacology.

[42]  Pearce,et al.  Transcriptional Repression of the 5‐HT1A Receptor Promoter by Corticosterone Via Mineralocorticoid Receptors Depends on the Cellular Context , 2000, Journal of neuroendocrinology.

[43]  O. Meijer,et al.  Corticosterone and serotonergic neurotransmission in the hippocampus: functional implications of central corticosteroid receptor diversity. , 1998, Critical reviews in neurobiology.

[44]  J. John Mann,et al.  Cortical 5-HT2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice , 2006, Science.

[45]  R. Parsey,et al.  Imaging the serotonin 1A receptor using [11C]WAY100635 in healthy controls and major depression , 2013, Philosophical Transactions of the Royal Society B: Biological Sciences.

[46]  Viktor Varga,et al.  Serotonergic neuron diversity: identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[47]  A. T. Gulledge,et al.  Serotonin and Prefrontal Cortex Function: Neurons, Networks, and Circuits , 2011, Molecular Neurobiology.

[48]  R. Hen,et al.  Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants , 2003, Science.

[49]  D. Wasserman,et al.  The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt , 2006, Behavioral and Brain Functions.

[50]  P. Albert,et al.  Cell‐type specific induction of tryptophan hydroxylase‐2 transcription by calcium mobilization , 2007, Journal of neurochemistry.

[51]  H. Gershenfeld,et al.  An exploratory factor analysis of the Tail Suspension Test in 12 inbred strains of mice and an F2 intercross , 2003, Brain Research Bulletin.

[52]  R. Porsolt,et al.  Use of latency to immobility improves detection of antidepressant-like activity in the behavioral despair test in the mouse. , 2009, European journal of pharmacology.

[53]  Pamela A. Silver,et al.  Cortical 5-HT 2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice , 2006 .

[54]  R. Corradetti,et al.  Suppression of Serotonin Neuron Firing Increases Aggression in Mice , 2013, The Journal of Neuroscience.

[55]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[56]  Benjamin D. Sachs,et al.  The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine , 2013, Translational Psychiatry.

[57]  R. Andrade,et al.  Serotonergic Regulation of Membrane Potential in Developing Rat Prefrontal Cortex: Coordinated Expression of 5-Hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 Receptors , 2004, The Journal of Neuroscience.

[58]  B. Lebowitz,et al.  Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. , 2006, The American journal of psychiatry.

[59]  H. Akil,et al.  Regulation of Hippocampal 5-HT1A Receptor Gene Expression by Dexamethasone , 1994, Neuropsychopharmacology.

[60]  H. Anisman,et al.  Increased Serotonin-1A (5-HT1A) Autoreceptor Expression and Reduced Raphe Serotonin Levels in Deformed Epidermal Autoregulatory Factor-1 (Deaf-1) Gene Knock-out Mice* , 2012, The Journal of Biological Chemistry.

[61]  E. Lambe,et al.  Enhanced Function of Prefrontal Serotonin 5-HT2 Receptors in a Rat Model of Psychiatric Vulnerability , 2010, The Journal of Neuroscience.

[62]  S. Dymecki,et al.  Projections and interconnections of genetically defined serotonin neurons in mice , 2012, The European journal of neuroscience.

[63]  P. Cohen,et al.  DEAF1 Is a Pellino1-interacting Protein Required for Interferon Production by Sendai Virus and Double-stranded RNA* , 2013, The Journal of Biological Chemistry.

[64]  M. Joëls,et al.  Effect of early life stress on serotonin responses in the hippocampus of young adult rats , 2004, Synapse.

[65]  W J Riedel,et al.  Serotonergic vulnerability and depression: assumptions, experimental evidence and implications , 2007, Molecular Psychiatry.

[66]  Paul Chen,et al.  Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex , 2008, Journal of Biological Chemistry.

[67]  V. Arango,et al.  Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice , 2003, Biological Psychiatry.

[68]  M. Austin,et al.  Human Freud-2/CC2D1B: A Novel Repressor of Postsynaptic Serotonin-1A Receptor Expression , 2009, Biological Psychiatry.

[69]  L H Parsons,et al.  Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[70]  D. Bright,et al.  Protein kinase C regulates tonic GABAA receptor-mediated inhibition in the hippocampus and thalamus , 2013, The European journal of neuroscience.

[71]  M. Millan The role of monoamines in the actions of established and "novel" antidepressant agents: a critical review. , 2004, European journal of pharmacology.

[72]  Andrew Holmes,et al.  Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease , 2008, Neuroscience & Biobehavioral Reviews.

[73]  P. Celada,et al.  The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. , 2004, Journal of psychiatry & neuroscience : JPN.

[74]  R. Hen,et al.  Behavioral / Systems / Cognitive Serotonin-1 A Autoreceptors Are Necessary and Sufficient for the Normal Formation of Circuits Underlying Innate Anxiety , 2011 .

[75]  Ahmad R. Hariri,et al.  Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits , 2010 .

[76]  D. Murphy,et al.  Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression , 2003, Biological Psychiatry.

[77]  Gabriele Flügge,et al.  5-HT1A receptor expression in pyramidal neurons of cortical and limbic brain regions , 2005, Cell and Tissue Research.

[78]  D. Wong,et al.  Case history: the discovery of fluoxetine hydrochloride (Prozac). , 2005, Nature reviews. Drug discovery.

[79]  P. Celada,et al.  5-HT1A receptor agonists enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. , 2012, Cerebral cortex.

[80]  R. Parsey,et al.  Imaging the serotonin 1 A receptor using [ 11 C ] WAY 100635 in healthy controls and major depression , 2013 .

[81]  E. Nestler,et al.  Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety: Behavioral and Biochemical Consequences of Isoform Targeting , 2008, Biological Psychiatry.

[82]  Nanxin Li,et al.  A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists , 2012, Philosophical Transactions of the Royal Society B: Biological Sciences.

[83]  M Toth,et al.  Increased anxiety of mice lacking the serotonin1A receptor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[84]  E. Deneris,et al.  Pet-1 is required across different stages of life to regulate serotonergic function , 2010, Nature Neuroscience.

[85]  P. Albert,et al.  Transcriptional regulation at a HTR1A polymorphism associated with mental illness , 2008, Neuropharmacology.

[86]  A. Rush,et al.  STAR*D , 2009, CNS drugs.

[87]  M. Caron,et al.  The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse , 2012, Philosophical Transactions of the Royal Society B: Biological Sciences.

[88]  C. Hamani,et al.  Preclinical Studies Modeling Deep Brain Stimulation for Depression , 2012, Biological Psychiatry.

[89]  A. Newman-Tancredi,et al.  P5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function , 2013, Psychopharmacology.

[90]  P. Albert,et al.  Modifying 5-HT1A Receptor Gene Expression as a New Target for Antidepressant Therapy , 2010, Front. Neurosci..

[91]  P. Celada,et al.  Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. , 2004, Cerebral cortex.

[92]  N. Kushwaha,et al.  A critical protein kinase C phosphorylation site on the 5‐HT1A receptor controlling coupling to N‐type calcium channels , 2002, The Journal of physiology.

[93]  D. E. Nichols,et al.  Serotonin receptors. , 2008, Chemical reviews.

[94]  V. Vaidya,et al.  Postnatal Fluoxetine-Evoked Anxiety Is Prevented by Concomitant 5-HT2A/C Receptor Blockade and Mimicked by Postnatal 5-HT2A/C Receptor Stimulation , 2014, Biological Psychiatry.

[95]  R. Lister The use of a plus-maze to measure anxiety in the mouse , 2004, Psychopharmacology.

[96]  Christine DeLorenzo,et al.  Antidepressant Treatment Reduces Serotonin-1A Autoreceptor Binding in Major Depressive Disorder , 2013, Biological Psychiatry.

[97]  M. Austin,et al.  Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress , 2009, Neuroscience.

[98]  H. Meltzer,et al.  Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. , 2012, Current pharmaceutical biotechnology.

[99]  John F. G. Atack,et al.  Serotonin Transporter , 2021, Encyclopedia of Evolutionary Psychological Science.

[100]  P. Albert Transcriptional regulation of the 5-HT1A receptor: implications for mental illness , 2012, Philosophical Transactions of the Royal Society B: Biological Sciences.

[101]  I. Lucki,et al.  5-HT1A receptor function in major depressive disorder , 2009, Progress in Neurobiology.

[102]  A. Bortolozzi,et al.  Acute 5-HT1A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions , 2012, Psychopharmacology.

[103]  J. Gugten,et al.  Effects of repeated testing in two inbred strains on flesinoxan dose-response curves in three mouse models for anxiety. , 2004, European journal of pharmacology.

[104]  Rene Hen,et al.  The developmental origins of anxiety , 2004, Nature Reviews Neuroscience.

[105]  A. Bortolozzi,et al.  Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects , 2012, Molecular Psychiatry.

[106]  R. Hen,et al.  Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice , 2004, Science.

[107]  A. Lakatos,et al.  Maternal separation alters serotonergic transporter densities and serotonergic 1A receptors in rat brain , 2006, Neuroscience.

[108]  P. Albert,et al.  Receptor signaling and structure: insights from serotonin-1 receptors , 2001, Trends in Endocrinology & Metabolism.

[109]  Dennis S. Charney,et al.  Neurobiological mechanisms in major depressive disorder , 2009, Canadian Medical Association Journal.

[110]  C. Benkelfat,et al.  Brain Serotonin Synthesis in Adult Males Characterized by Physical Aggression during Childhood: A 21-Year Longitudinal Study , 2010, PloS one.

[111]  S. Watson,et al.  Regulation of Serotonin1A, Glucocorticoid, and Mineralocorticoid Receptor in Rat and Human Hippocampus: Implications for the Neurobiology of Depression , 1998, Biological Psychiatry.

[112]  P. Albert,et al.  Freud‐2/CC2D1B mediates dual repression of the serotonin‐1A receptor gene , 2011, The European journal of neuroscience.

[113]  Jacqueline N. Crawley,et al.  Reduced aggression in mice lacking the serotonin transporter , 2002, Psychopharmacology.

[114]  T. Vos,et al.  Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010 , 2013, The Lancet.

[115]  H. Anisman,et al.  Increased Serotonin-1 A ( 5-HT 1 A ) Autoreceptor Expression and Reduced Raphe Serotonin Levels in Deformed Epidermal Autoregulatory Factor-1 ( Deaf-1 ) Gene Knock-out Mice * , 2012 .

[116]  Zoe R. Donaldson,et al.  Genetic approaches for understanding the role of serotonin receptors in mood and behavior , 2013, Current Opinion in Neurobiology.

[117]  René Hen,et al.  Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult , 2002, Nature.

[118]  Susanne E. Ahmari,et al.  Flexible Accelerated STOP Tetracycline Operator-Knockin (FAST): A Versatile and Efficient New Gene Modulating System , 2010, Biological Psychiatry.

[119]  S. Easteal,et al.  No association between the serotonin-1A receptor gene single nucleotide polymorphism rs6295C/G and symptoms of anxiety or depression, and no interaction between the polymorphism and environmental stressors of childhood anxiety or recent stressful life events on anxiety or depression , 2010, Psychiatric genetics.

[120]  D. Murphy,et al.  Are serotonin transporter knockout mice ‘depressed’?: hypoactivity but no anhedonia , 2006, Neuroreport.

[121]  D. Denys,et al.  [Deep brain stimulation for psychiatric disorders]. , 2018, Nederlands tijdschrift voor geneeskunde.

[122]  K. Jacobsen,et al.  HES1 regulates 5-HT1A receptor gene transcription at a functional polymorphism: Essential role in developmental expression , 2008, Molecular and Cellular Neuroscience.

[123]  N. Kushwaha,et al.  Coupling of 5‐HT1A autoreceptors to inhibition of mitogen‐activated protein kinase activation via Gβγ subunit signaling , 2005 .

[124]  G. Mengod,et al.  Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. , 2004, Cerebral cortex.

[125]  René Hen,et al.  5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants , 2010, Neuron.

[126]  P. Albert,et al.  Cell-Specific Repressor or Enhancer Activities of Deaf-1 at a Serotonin 1A Receptor Gene Polymorphism , 2006, The Journal of Neuroscience.

[127]  P. Debata,et al.  Serotonin 1A receptor-mediated signaling through ERK and PKCα is essential for normal synaptogenesis in neonatal mouse hippocampus , 2012, Translational Psychiatry.

[128]  D. Wong,et al.  The Discovery of Fluoxetine Hydrochloride (Prozac) , 2005, Nature Reviews Drug Discovery.

[129]  E. Smeraldi,et al.  Association of the C(-1019)G 5-HT1A promoter polymorphism with exposure to stressors preceding hospitalization for bipolar depression. , 2011, Journal of affective disorders.

[130]  P. Albert,et al.  Multiple phosphorylation sites are required for pathway-selective uncoupling of the 5-hydroxytryptamine1A receptor by protein kinase C. , 1995, Molecular pharmacology.

[131]  P. Celada,et al.  Preferential in vivo action of F15599, a novel 5‐HT1A receptor agonist, at postsynaptic 5‐HT1A receptors , 2010, British journal of pharmacology.

[132]  M. Austin,et al.  17β-Estradiol-Induced Regulation of the Novel 5-HT1A-Related Transcription Factors NUDR and Freud-1 in SH SY5Y Cells , 2012, Cellular and Molecular Neurobiology.

[133]  Eric J. Nestler,et al.  The molecular neurobiology of depression , 2008, Nature.

[134]  Zhen Yan,et al.  Serotonin 5-HT1A Receptors Regulate AMPA Receptor Channels through Inhibiting Ca2+/Calmodulin-dependent Kinase II in Prefrontal Cortical Pyramidal Neurons* , 2002, The Journal of Biological Chemistry.

[135]  Kirsten Schmieder,et al.  Association of serotonin-1A and -2A receptor promoter polymorphisms with depressive symptoms, functional recovery, and pain in patients 6months after lumbar disc surgery , 2013, PAIN®.

[136]  M. Åsberg,et al.  Neurotransmitters and Suicidal Behavior , 1997, Annals of the New York Academy of Sciences.

[137]  A. Serretti,et al.  The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder , 2013, European Archives of Psychiatry and Clinical Neuroscience.

[138]  B. Gutiérrez,et al.  Polymorphic variation at the serotonin 1-A receptor gene is associated with comorbid depression and generalized anxiety , 2011, Psychiatric genetics.

[139]  Rebecca Elliott,et al.  The HTR1A and HTR1B receptor genes influence stress-related information processing , 2011, European Neuropsychopharmacology.

[140]  G. Mengod,et al.  Serotonin 1A receptors in human and monkey prefrontal cortex are mainly expressed in pyramidal neurons and in a GABAergic interneuron subpopulation: implications for schizophrenia and its treatment , 2008, Journal of neurochemistry.

[141]  G. Rajkowska,et al.  Decreased expression of Freud-1/CC2D1A, a transcriptional repressor of the 5-HT1A receptor, in the prefrontal cortex of subjects with major depression. , 2010, The international journal of neuropsychopharmacology.

[142]  Jeremy Veenstra-VanderWeele,et al.  Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior , 2012, Proceedings of the National Academy of Sciences.

[143]  Wade G. Regehr,et al.  Linking Genetically Defined Neurons to Behavior through a Broadly Applicable Silencing Allele , 2009, Neuron.

[144]  E. Audero,et al.  Serotonin 1A auto‐receptors are not sufficient to modulate anxiety in mice , 2013, The European journal of neuroscience.

[145]  S. Turley,et al.  Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes , 2009, Nature Immunology.

[146]  P. Albert,et al.  Freud-1: A Neuronal Calcium-Regulated Repressor of the 5-HT1A Receptor Gene , 2003, The Journal of Neuroscience.

[147]  Alan D. Lopez,et al.  The Global Burden of Disease Study , 2003 .

[148]  K. Deisseroth,et al.  A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge , 2012, Nature.

[149]  Sanbing Shen,et al.  Increased Expression of the 5-HT Transporter Confers a Low- Anxiety Phenotype Linked to Decreased 5-HT Transmission , 2006, The Journal of Neuroscience.