Mecanismos moleculares de la esquizofrenia

Contenido principal del artículo

Nicolás Laverde
https://orcid.org/0000-0002-9756-0834
Angela Lizeth Giraldo Serna
https://orcid.org/0000-0002-3310-8718
Lina Vanessa Becerra Hernández
https://orcid.org/0000-0002-4468-6716

Resumen

La etiología de la esquizofrenia no está totalmente dilucidada. Se conocen más de 100 diferentes loci de genes relacionados con esquizofrenia, la mayoría de los cuales codifican moléculas asociados a los sistemas de neurotransmisores o al neurodesarrollo. Las primeras abarcan receptores de los neurotransmisores como dopamina, GABA o glutamato y de otros neurotransmisores con menor relación, como la serotonina y la acetilcolina. También están implicadas diversas enzimas relacionadas con el metabolismo, cotransportadores y algunas proteínas intracelulares involucradas en la degradación o síntesis de dichos neurotransmisores. Entre las moléculas que intervienen en el neurodesarrollo están los factores neurotróficos (BDNF, DISC1, NRG1) y las proteínas del complemento C3 y C4, que median la respuesta inflamatoria y la poda sináptica durante el desarrollo temprano. Los productos de la producción genética involucrados en la etiología de la esquizofrenia aportan a la vulnerabilidad selectiva o al proceso de lesión que se instaura o progresa en el paciente, por tanto, su estudio es de relevancia para la comprensión de los fenómenos clínicos propios de la enfermedad.

Palabras clave:
esquizofrenia genes trastornos del neurodesarrollo neurotransmisores biología molecular

Citas

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5a ed. Washington: American Psychiatric Publishing; 2013.

McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—An overview. JAMA Psychiatry. 2020;77(2):201–10.

Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019;381(18):1753-61.

Zamanpoor M. Schizophrenia in a genomic era: A review from the pathogenesis, genetic and environmental etiology to diagnosis and treatment insights. Psychiatr Genet. 2020;30(1):1-9.

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421-7.

McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: From biology to symptoms. Trends Neurosci. 2019;42(3):205-20.

Saiz J, Vega D C, Sánchez P. Bases neurobiológicas de la esquizofrenia. Clínica y Salud. 2010;21(3):235-54.

Kahn RS. On the origins of schizophrenia. Am J Psychiatry. 2020;177(4):291-297.

Aringhieri S, Carli M, Kolachalam S, Verdesca V, Cini E, Rossi M, et al. Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences. Pharmacol Ther. 2018;192:20-41.

Álvarez-Restrepo JF, Becerra L. Papel del receptor nicotínico Alfa4Beta2 en neuroprotección para la enfermedad de Parkinson, una revisión de la literatura. Salutem Scientia Spiritus 2019;5(2):57-60.

Liu Y, Hao S, Yang B, Fan Y, Qin X, Chen Y, et al. Wnt/β-catenin signaling plays an essential role in α7 nicotinic receptor-mediated neuroprotection of dopaminergic neurons in a mouse Parkinson’s disease model. Biochem Pharmacol. 2017;140:115-123.

Uno Y, Coyle JT. Glutamate hypothesis in schizophrenia. Psychiatry Clin Neurosci. 2019;73(5):204- 215.

Stahl SM. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: Dopamine, serotonin, and glutamate. CNS Spectr. 2018;23(3):187-191.

Conio B, Martino M, Magioncalda P, Escelsior A, Inglese M, Amore M, et al. Opposite effects of dopamine and serotonin on resting-state networks: Review and implications for psychiatric disorders. Mol Psychiatry. 2020;25(1):82-93.

García-Anaya M, Apiquián, R, Fresán A. Los antipsicóticos atípicos: Una revisión. Salud Mental. 2001;24:37-43.

Shetty AK, Bates A. Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer’s and Parkinson’s diseases. Brain Res. 2016;1638(Pt A):74-87.

Chiapponi C, Piras F, Piras F, Caltagirone C, Spalletta G. GABA system in schizophrenia and mood disorders: A mini review on third-generation imaging studies. Front Psychiatry. 2016;7:61.

Schmidt MJ, Mirnics K. Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology.

;40(1):190-206. 19. Hoftman GD, Volk DW, Bazmi HH, Li S, Sampson AR, Lewis DA. Altered cortical expression of GABA-related genes in schizophrenia: Illness progression vs developmental disturbance. Schizophr Bull. 2015;41(1):180-91.

Hoftman GD, Volk DW, Bazmi HH, Li S, Sampson AR, Lewis DA. Altered cortical expression of GABA-related genes in schizophrenia: Illness progression vs developmental disturbance. Schizophr Bull. 2015;41(1):180-91.

Maldonado-Aviles JG, Curley AA, Hashimoto T, Morrow AL, Ramsey AJ, O’Donnell P, et al. Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia. Am J Psychiatry. 2009;166:450–9

Wang H, Farhan M, Xu J, Lazarovici P, Zheng W. The involvement of DARPP-32 in the pathophysiology of schizophrenia. Oncotarget. 2017;8(32):53791-803.

Peters SK, Dunlop K, Downar J. Cortico-striatal-thalamic loop circuits of the salience network: A central pathway in psychiatric disease and treatment. Front Syst Neurosci. 2016;10:104.

Petanjek Z, Judaš M, Šimic G, Rasin MR, Uylings HB, Rakic P, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci USA. 2011;108(32):13281–6.

Elston GN, Oga T, Fujita I. Spinogenesis and pruning scales across functional hierarchies. J. Neurosci. 2009;29(10):3271–5.

Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res. 1979;163(2):195–205.

Álvarez-Lombana A, Becerra-Hernández LV. La esquizofrenia como una alteración del neurodesarrollo. Sal Sci Spir. 2020;6(2):60-63.

Wang HY, Liu Y, Yan JW, Hu XL, Zhu DM, Xu XT, Li XS. Gene polymorphisms of DISC1 is associated with schizophrenia: Evidence from a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 81:64-73.

Woo JJ, Pouget JG, Zai CC, Kennedy JL. The complement system in schizophrenia: Where are we now and what’s next? Mol Psychiatry. 2020;25(1):114-130.

Feinberg I. Adolescence and mental illness. Science. 1987;236(4801):507-8.

Roberts RC, Roche JK, Conley RR. Synaptic differences in the patch matrix compartments of subjects with schizophrenia: A postmortem ultrastructural study of the striatum. Neurobiol Dis. 2005;20(2):324-35.

Nieto RR, Carrasco A, Corral S, Castillo R, Gaspar PA, Bustamante ML, et al. BDNF as a biomarker of cognition in schizophrenia/psychosis: An updated review. Front Psychiatry. 2021;12:662407.

Dahoun T, Trossbach SV, Brandon NJ, Korth C, Howes OD. The impact of disrupted-inschizophrenia 1 (DISC1) on the dopaminergic system: A systematic review. Transl Psychiatry. 2017;7(1):e1015.

Tomoda T, Hikida T, Sakurai T. Role of DISC1 in neuronal trafficking and its implication in neuropsychiatric manifestation and neurotherapeutics. Neurotherapeutics. 2017;14(3):623-9.

Wang M, Zhang L, Gage FH. Microglia, complement and schizophrenia. Nat Neurosci. 2019;22(3):333–4.

Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22(3):374–85.

Jones MC, Koh JM, Cheong KH. Synaptic pruning in schizophrenia: Does minocycline modulate psychosocial brain development? Bioessays. 2020;42(9):e2000046.

Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M. Neurotrophin expression in rat hippocampal slices: A stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron. 1992;9:1081–8.

Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92:8856–60.

Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223-50.

Schmidt-Kastner R, van Os J, Esquivel G, Steinbusch HW, Rutten BP. An environmental analysis of genes associated with schizophrenia: Hypoxia and vascular factors as interacting elements in the neurodevelopmental model. Mol Psychiatry. 2012;17:1194–205.

Peng S, Li W, Lv L, Zhang Z, Zhan X. BDNF as a biomarker in diagnosis and evaluation of treatment for schizophrenia and depression. Discov Med. 2018;26(143):127-36.

Heitz U, Papmeyer M, Studerus E, Egloff L, Ittig S, Andreou C, et al. Plasma and serum brainderived neurotrophic factor (BDNF) levels and their association with neurocognition in at-risk mental state, first episode psychosis and chronic schizophrenia patients. World J Biol Psychiatry. 2019;20(7):545-554.

Notaras M, Hill R, van den Buuse M. ¿A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev. 2015;51:15-30.

Di Carlo P, Punzi G, Ursini G. Brain-derived neurotrophic factor and schizophrenia. Psychiatr Genet. 2020;29(5):200-10.

Niitsu T, Ishima T, Yoshida T, Hashimoto T, Matsuzawa D, Shirayama Y, et al. A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia. Psychiatry Res. 2014;215(2):268-73.

Lu B, Martinowich K. Cell biology of BDNF and its relevance to schizophrenia. Novartis Found Symp. 2008;289:119-29. 47. Dunham JS, Deakin JF, Miyajima F, Payton A, Toro CT. Expression of hippocampal brainderived neurotrophic factor and its receptors in Stanley consortium brains. J Psychiatr Res. 2009;43(14):1175-84.

Lin Z, Su Y, Zhang C, Xing M, Ding W, Liao L, et al. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. Plos One. 2013;8(9):e74264.

Kuo CY, Lin CH, Lane HY. Molecular basis of late-life depression. Int J Mol Sci. 2021;22(14):7421.

Online Mendelian Inheritance in Man, OMIM® [Internet]. Baltimore: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University; 2022. Disponible en: https://omim.org/

Detalles del artículo

Biografía del autor/a

Nicolás Laverde, Pontificia Universidad Javeriana

Miembro del Semillero de Innovadores en Salud, ISSEM PUJ Cali, Facultad de Ciencias de la Salud, Pontificia Universidad Javeriana.

Angela Lizeth Giraldo Serna, Pontificia Universidad Javeriana Cali

Miembro del Semillero de Innovadores en Salud, ISSEM PUJ Cali, Facultad de Ciencias de la Salud, Pontificia Universidad Javeriana.

Lina Vanessa Becerra Hernández, Pontificia Universidad Javeriana Cali

Miembro del grupo de Investigación en Ciencias Básicas y Clínicas de la Salud, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Pontificia Universidad Javeriana.