A mutação espontânea tremor (tr) , autossômica recessiva, foi identificada na colônia de camundongos Swiss no Biotério do Departamento de Patologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo. Os mutantes apresentaram como principais características fenotípicas tremores, ataxia e convulsões tônicas audiogênicas. Por meio de dez retrocruzamentos essa mutação foi transferida para a linhagem congênica C57BL/6 (N10). O mapeamento genético com marcadores microssatélites distribuídos pelo genoma do camundongo indicou que a mutação tr encontra-se no cromossomo 14, na região entre 33,21 e 38,21 cM, tendo como possível candidato o gene Egr3 (Early Growth Response 3). O presente estudo teve como objetivo caracterizar o fenótipo comportamental do camundongo mutante tremor. A caracterização do fenótipo dos camundongos mutantes Swiss foi realizada a partir do nascimento até a idade adulta. Os parâmetros do desenvolvimento físico analisados foram: desdobramento das orelhas, erupção dos dentes incisivos, abertura dos olhos, surgimento da pelagem completa, ganho de peso e comprimento dos filhotes e desenvolvimento sexual. No desenvolvimento reflexológico foram analisados: preensão palmar, geotaxia negativa, endireitamento de postura e sobressalto. No 21&ordem; dia de vida foi realizado o teste de campo aberto para analisar a atividade geral dos animais, e no 60&ordem; dia esse teste foi repetido, juntamente com testes para analisar parâmetros comportamentais. Os testes realizados em campo aberto foram ordenados por parâmetro avaliado; 1) atividade geral dos animais e sistema sensorial: frêmito vocal, irritabilidade, reflexo auricular, aperto de cauda, reflexo corneal e resposta ao toque; 2) testes psicomotores: trem posterior, reflexo de endireitamento, tônus corporal e força de agarrar; 3) avaliação do sistema nervoso central: tremores, cauda em pé, micção e defecação. Demais testes realizados analisaram: comportamento em labirinto em cruz elevada, coordenação motora em trave elevada, memória espacial no labirinto em T, e respostas comportamentais nos testes de natação forçada e de suspensão pela cauda. Exceto pelo menor peso no desmame, os parâmetros de desenvolvimento analisados não apresentaram diferenças significativas entre os mutantes e controles, o que confirmou a hipótese de que as alterações fenotípicas somente são perceptíveis a partir de 3 semanas de vida. A caracterização comportamental do fenótipo também foi realizada nos mutantes em fundo genético C57BL/6, de ambos os sexos, com 8 semanas de idade. Em relação aos camundongos controle, nos mutantes houve aumento da presença de cauda em pé, da ataxia e do tremor; menor frequência de levantar e de limpeza do corpo (grooming); redução da coordenação motora, indicando evidente prejuízo motor. Também foram observadas respostas negativas à ansiedade e hiperatividade, mas não houve alteração na memória espacial dos mutantes. Os resultados indicaram que o mutante tremor apresentou prejuízos de origem no sistema nervoso central; demostraram também que o fenótipo observado coincide com as alterações descritas na literatura, sugerindo o gene Egr3 como possível candidato para a mutação. A caracterização fenotípica desse animal é importante no entendimento das alterações causadas pela mutação e se essa apresenta potencial como modelo para doenças neurológicas. / The autosomal recessive spontaneous mutation tremor (tr) was identified in the Swiss mice colony of the laboratory animal facility of the Department of Pathology, from Faculdade de Medicina Veterinária e Zootecnia - Universidade de São Paulo. The mutants presented tremors, ataxia and audiogenic tonic convulsions as the main expressive characteristics. This mutation was moved from Swiss onto C57BL/6 by ten backcrosses (N10). Genetic mapping with microsatellite markers distributed through the mouse genome showed that the mutation is on 14 chromosome, between 33.21 and 38.21 cM, making Egr3 (Early Growth Response 3) a candidate gene. This study aimed to characterize the behavior phenotype of the tremor mice. Phenotypic characterization of the Swiss mutant mice was performed from birth to adulthood. The physical development points analyzed were: unfolding of the ears, eruption of the incisor teeth, opening the eyes, complete fur, weight gain and length, and sexual development. The reflexology development ones were: palmar grip, negative geotaxia, posture straightening and reaction to sound. On the 21day-old the open field test was performed to analyze the activity of the animals, and on the 60-day-old this task was repeated along with tests to analyze behavioral parameters. The tests performed in the open field were evaluated by parameters; 1) general activity and sensory system: vocalization, irritability, auricular reflex, tail flick, corneal reflex and response to touch; 2) psychomotor tests: hindquarter fall, surface-rightingreflex, body tone and grasping strength; 3) evaluation of the central nervous system: tremors, straub tail, micturitionand defecation. Other tests analyzed: behavior in elevated plus maze, motor coordination in balance beam test, spatial memory in T maze alternation test, and behavioral responses in forced swing and tail suspension tests. Except for the lower weight at weaning, the development parameters analyzed did not show significant differences between the mutants and controls, which confirmed the hypothesis that phenotypic changes are only perceptible after 3weeks-old. The behavioral characterization of the phenotype was also performed on 8-week-old C57BL/6 mutants of both sexes. In comparison to the control mice, in the mutants there were an increase in the presence of straub tail, ataxia and tremor; less frequent rearing and grooming; less motor coordination, indicating evident motor impairment. Negative responses to anxiety and hyperactivity were also observed, but there was no change in the spatial memory of the mutants. The results indicated that the tremor mutant presented damages in the central nervous system; also showed that the phenotype coincides with the changes described in the literature, suggesting the Egr3 gene as a possible candidate for the mutation. The phenotypic characterization of this animal is important to clarify impairments caused by the genetic mutation, and also identify if this potential model could be useful to study neurological diseases.

A mutação espontânea tremor (tr) , autossômica recessiva, foi identificada na colônia de camundongos Swiss no Biotério do Departamento de Patologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo. Os mutantes apresentaram como principais características fenotípicas tremores, ataxia e convulsões tônicas audiogênicas. Por meio de dez retrocruzamentos essa mutação foi transferida para a linhagem congênica C57BL/6 (N10). O mapeamento genético com marcadores microssatélites distribuídos pelo genoma do camundongo indicou que a mutação tr encontra-se no cromossomo 14, na região entre 33,21 e 38,21 cM, tendo como possível candidato o gene Egr3 (Early Growth Response 3). O presente estudo teve como objetivo caracterizar o fenótipo comportamental do camundongo mutante tremor. A caracterização do fenótipo dos camundongos mutantes Swiss foi realizada a partir do nascimento até a idade adulta. Os parâmetros do desenvolvimento físico analisados foram: desdobramento das orelhas, erupção dos dentes incisivos, abertura dos olhos, surgimento da pelagem completa, ganho de peso e comprimento dos filhotes e desenvolvimento sexual. No desenvolvimento reflexológico foram analisados: preensão palmar, geotaxia negativa, endireitamento de postura e sobressalto. No 21&ordem; dia de vida foi realizado o teste de campo aberto para analisar a atividade geral dos animais, e no 60&ordem; dia esse teste foi repetido, juntamente com testes para analisar parâmetros comportamentais. Os testes realizados em campo aberto foram ordenados por parâmetro avaliado; 1) atividade geral dos animais e sistema sensorial: frêmito vocal, irritabilidade, reflexo auricular, aperto de cauda, reflexo corneal e resposta ao toque; 2) testes psicomotores: trem posterior, reflexo de endireitamento, tônus corporal e força de agarrar; 3) avaliação do sistema nervoso central: tremores, cauda em pé, micção e defecação. Demais testes realizados analisaram: comportamento em labirinto em cruz elevada, coordenação motora em trave elevada, memória espacial no labirinto em T, e respostas comportamentais nos testes de natação forçada e de suspensão pela cauda. Exceto pelo menor peso no desmame, os parâmetros de desenvolvimento analisados não apresentaram diferenças significativas entre os mutantes e controles, o que confirmou a hipótese de que as alterações fenotípicas somente são perceptíveis a partir de 3 semanas de vida. A caracterização comportamental do fenótipo também foi realizada nos mutantes em fundo genético C57BL/6, de ambos os sexos, com 8 semanas de idade. Em relação aos camundongos controle, nos mutantes houve aumento da presença de cauda em pé, da ataxia e do tremor; menor frequência de levantar e de limpeza do corpo (grooming); redução da coordenação motora, indicando evidente prejuízo motor. Também foram observadas respostas negativas à ansiedade e hiperatividade, mas não houve alteração na memória espacial dos mutantes. Os resultados indicaram que o mutante tremor apresentou prejuízos de origem no sistema nervoso central; demostraram também que o fenótipo observado coincide com as alterações descritas na literatura, sugerindo o gene Egr3 como possível candidato para a mutação. A caracterização fenotípica desse animal é importante no entendimento das alterações causadas pela mutação e se essa apresenta potencial como modelo para doenças neurológicas. / The autosomal recessive spontaneous mutation tremor (tr) was identified in the Swiss mice colony of the laboratory animal facility of the Department of Pathology, from Faculdade de Medicina Veterinária e Zootecnia - Universidade de São Paulo. The mutants presented tremors, ataxia and audiogenic tonic convulsions as the main expressive characteristics. This mutation was moved from Swiss onto C57BL/6 by ten backcrosses (N10). Genetic mapping with microsatellite markers distributed through the mouse genome showed that the mutation is on 14 chromosome, between 33.21 and 38.21 cM, making Egr3 (Early Growth Response 3) a candidate gene. This study aimed to characterize the behavior phenotype of the tremor mice. Phenotypic characterization of the Swiss mutant mice was performed from birth to adulthood. The physical development points analyzed were: unfolding of the ears, eruption of the incisor teeth, opening the eyes, complete fur, weight gain and length, and sexual development. The reflexology development ones were: palmar grip, negative geotaxia, posture straightening and reaction to sound. On the 21day-old the open field test was performed to analyze the activity of the animals, and on the 60-day-old this task was repeated along with tests to analyze behavioral parameters. The tests performed in the open field were evaluated by parameters; 1) general activity and sensory system: vocalization, irritability, auricular reflex, tail flick, corneal reflex and response to touch; 2) psychomotor tests: hindquarter fall, surface-rightingreflex, body tone and grasping strength; 3) evaluation of the central nervous system: tremors, straub tail, micturitionand defecation. Other tests analyzed: behavior in elevated plus maze, motor coordination in balance beam test, spatial memory in T maze alternation test, and behavioral responses in forced swing and tail suspension tests. Except for the lower weight at weaning, the development parameters analyzed did not show significant differences between the mutants and controls, which confirmed the hypothesis that phenotypic changes are only perceptible after 3weeks-old. The behavioral characterization of the phenotype was also performed on 8-week-old C57BL/6 mutants of both sexes. In comparison to the control mice, in the mutants there were an increase in the presence of straub tail, ataxia and tremor; less frequent rearing and grooming; less motor coordination, indicating evident motor impairment. Negative responses to anxiety and hyperactivity were also observed, but there was no change in the spatial memory of the mutants. The results indicated that the tremor mutant presented damages in the central nervous system; also showed that the phenotype coincides with the changes described in the literature, suggesting the Egr3 gene as a possible candidate for the mutation. The phenotypic characterization of this animal is important to clarify impairments caused by the genetic mutation, and also identify if this potential model could be useful to study neurological diseases.

While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR) hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD). Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3), early growth response 1 (EGR1) and NGFI-A Binding Protein 2 (NAB2); each of which contains the "Index single nucleotide polymorphism (SNP)" (most SNP) at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may result in insufficient electrophysiologic, immunologic, and neuroprotective, processes that these genes normally mediate. Continued adverse environmental experiences, over time, may thereby result in neuropathology that gives rise to the symptoms of schizophrenia. By combining multiple genes associated with schizophrenia susceptibility, in a functional cascade triggered by neuronal activity, the proposed biological pathway provides an explanation for both the polygenic and environmental influences that determine the complex etiology of this mental illness.

Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 (EGR3) of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that EGR3 expression is induced by brain-derived neurotrophic factor (BDNF) that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.