Abstract
Patients with psychiatric disease are diagnosed by psychiatrists based on the information of non-quantitative objective parameters, including behavioral phenotypes. However, how any neural mechanism affects such behavioral phenotypes in patients is still unclear. Recent functional studies suggested the alteration in brain neural/network activity responds to subjected stimuli in some brain regions of psychiatric patients, indicating that excitatory/inhibitory (E/I) imbalance occurs in local neural circuits responsible for regional activities. Moreover, in human genetics, a large number of genetic variations, including single nucleotide variation (SNV) and copy number variation (CNV), have been found in psychiatric patients. Such variations must be causes of a psychiatric behavioral phenotype, while understanding of the relationship between genetic variations and neural mechanisms underlying psychiatric behavior remains poor due to the heterogeneity in genetic variations. Functional and molecular analyses with SNV and CNV suggest the mutations of synaptic genes might contribute to the abnormal neural activity due to synaptic dysfunction. To overcome the sparse knowledge of psychiatric neural phenotypes, we can choose two ways: one is to detect the abnormalities of neural function in animal models with the genetic variations found in human genetics, which means construct validity of an animal model, and another is to reproduce the behavioral phenotypes seen in psychiatric disorders by artificially controlling neural functions, referred to as face validity. Analyzing the neural activity in animal models with construct and face validities would help us understand the neural state in psychiatric patients.
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References
Blundell J, Tabuchi K, Bolliger MF et al (2009) Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav 8:114–126
Cardin JA, Carlen M, Meletis K et al (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459:663–667
Carlen M, Meletis K, Siegle H et al (2012) A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol Psychiatry 17:537–548
Chao HT, Chen H, Samaco RC et al (2010) Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468:263–269
Chaudhury D, Walsh JJ, Friedman AK et al (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532–536
Covington HE 3rd, Lobo MK, Maze I et al (2010) Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 30:16082–16090
Cross-Disorder Group of the Psychiatric Genomics (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–994
Dani VS, Chang Q, Maffei A et al (2005) Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A 102:12560–12565
Etherton M, Foldy C, Sharma M et al (2011) Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc Natl Acad Sci U S A 108:13764–13769
Fatemi SH, Halt AR, Stary JM et al (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52:805–810
Gibson JR, Bartley AF, Hays SA et al (2008) Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J Neurophysiol 100:2615–2626
Gkogkas CG, Khoutorsky A, Ran I et al (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371–377
Gogolla N, Leblanc JJ, Quast KB et al (2009) Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1:172–181
Han S, Tai C, Westenbroek RE et al (2012) Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489:385–390
Hines RM, Wu L, Hines DJ et al (2008) Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression. J Neurosci 28:6055–6067
Konermann S, Brigham MD, Trevino AE et al (2013) Optical control of mammalian endogenous transcription and epigenetic states. Nature 500:472–476
Krishnan V, Han MH, Graham DL et al (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404
Liu X, Takumi T (2014) Genomic and genetic aspects of autism spectrum disorder. Biochem Biophys Res Commun 452:244–253
Lozano AM, Mayberg HS, Giacobbe P et al (2008) Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461–467
Malhotra D, Sebat J (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:1223–1241
McConnell MJ, Lindberg MR, Brennand KJ, Piper JC et al (2013) Mosaic copy number variation in human neurons. Science 342:632–637
Nakatani J, Tamada K, Hatanaka F et al (2009) Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137:1235–1246
Peca J, Feliciano C, Ting JT et al (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–442
Poulopoulos A, Aramuni G, Meyer G et al (2009) Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 63:628–642
Schaaf CP, Zoghbi HY (2011) Solving the autism puzzle a few pieces at a time. Neuron 70:806–808
Schmeisser MJ, Ey E, Wegener S et al (2012) Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486:256–260
Sullivan PF, Daly MJ, O’Donovan M (2012) Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 13:537–551
Tabuchi K, Blundell J, Etherton MR et al (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76
Tye KM, Deisseroth K (2012) Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci 13:251–266
Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11:100–113
Wallace ML, Burette AC, Weinberg RJ et al (2012) Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron 74:793–800
Wang X, Carlen M (2012) Optogenetic dissection of cortical information processing-shining light on schizophrenia. Brain Res 1476:31–37
Wang F, Zhu J, Zhu H et al (2011) Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science 334:693–697
Won H, Lee HR, Gee HY et al (2012) Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486:261–265
Won H, Mah W, Kim E (2013) Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci 6:19
Yang M, Bozdagi O, Scattoni ML et al (2012) Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci 32:6525–6541
Yizhar O, Fenno LE, Prigge M et al (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477:171–178
Acknowledgment
Our work was supported in part by the Japan Society of Promotion of Science and Ministry of Education, Culture, Sports, Science, and Technology KAKENHI, Strategic International Coorperative Program and CREST, Japan Science and Technology Agency and the Israel Ministry of Science and Technology.
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Nakai, N., Yizhar, O., Takumi, T. (2015). Towards Understanding the Neural Mechanism of Behavioral Phenotypes Seen in Psychiatric Disorders. In: Yawo, H., Kandori, H., Koizumi, A. (eds) Optogenetics. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55516-2_23
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DOI: https://doi.org/10.1007/978-4-431-55516-2_23
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