L’implication des récepteurs 5-HT1A dans la physiopathologie de la schizophrénie a été suggérée par de nombreuses études post mortem et pharmacologiques. Le développement d’études exploratoires du système sérotoninergique 5-HT1A chez des patients schizophrènes permet de préciser le rôle des récepteurs 5-HT1A dans la physiopathologie de la maladie et d’envisager de nouvelles stratégies thérapeutiques. L'existence du p-[18F]MPPF, radioligand ayant une affinité spécifique pour les récepteurs 5-HT1A, nous a permis de réaliser une exploration du système sérotoninergique 5-HT1A in vivo en tomographie par émission de positons (TEP) chez 19 patients schizophrènes et de comparer les résultats obtenus aux images de 19 témoins issus de la banque de données du CERMEP (Lyon). Notre premier objectif a été de mettre en évidence d’éventuelles différences de répartition de potentiel de liaison (BP) entre les patients et les témoins. Une diminution significative du [18F]MPPF BPND au niveau des régions frontales et orbitofrontales a été retrouvée chez les patients schizophrènes par rapport aux témoins. Dans un second temps, la comparaison des images TEP obtenues chez les patients selon que le traitement antipsychotique reçu a une action agoniste 5-HT1A (aripiprazole) ou en soit dépourvu (olanzapine, rispéridone) a montré une diminution plus importante du [18F]MPPF BPND chez les patients traités par aripiprazole que chez les patients traités par d’autres antipsychotiques, soulignant ainsi l’impact in vivo de ce traitement sur le système sérotoninergique 5-HT1A. Notre étude est la première, à notre connaissance, à utiliser le p-[18F]MPPF chez des patients schizophrènes / Backgrounds: Multiple post-mortem and pharmacological studies suggest a key role of the serotonergic 1A (5-HT1A) system in the pathophysiology of schizophrenia. Materials and methods: The aim of our work was to assess the 5-HT1A receptors availability In patients suffering from schizophrenia treated with different antipsychotic drugs, compared to controls, using a new ligand antagonist of 5-HT1A receptors, the [18F]MPPF. The 5-HT1A binding potential of 19 schizophrenic patients (treated with either aripiprazole (a 5-HT1A partial agonist) or Second Generation Antipsychotic (olanzapine or risperidone) was compared with that of 19 age-matched healthy controls. This is the first report of a [18F]MPPF PET study in treated patients with schizophrenia. Results: A significant reduction of [18F]MPPF BPND was found in treated patients with schizophrenia compared to age- and gender-matched healthy subjects. These modifications were mainly localized in the frontal and orbitofrontal cortex and may reflect either the pathophysiology of schizophrenia or medication effects. In comparison to matched healthy subjects, the reduction of 5-HT1A receptor availability was more extensive in schizophrenic patients with aripiprazole treatment than in schizophrenic patients with SGA treatment. Conclusion: These results suggest that aripiprazole has a major impact on [18F]MPPF BPND, likely due to its partial agonist activity at 5-HT1A receptors. In order to distinguish the relative contributions of the disease itself versus medication effects, future [18F]MPPF studies should be performed in APD-naïve patients with schizophrenia

A presente pesquisa pretende mostrar que a participação de polimorfismos específicos podem favorecer ou fornecer uma vulnerabilidade maior a determinados indivíduos que, quando submetidos a condições específicas de estresse, podem tentar o suicídio. Nos últimos anos, vem crescendo na literatura científica o número de estudos que demonstram que o cérebro de vítimas de suicídio apresenta uma alteração nos receptores de serotonina. Este estudo teve como objetivo verificar a frequência dos polimorfismos dos receptores de serotonina 5-HT1A e 5-HT2A, em pacientes deprimidos que tentaram o suicídio e em um grupo controle sem doença psiquiátrica. O trabalho foi desenvolvido utilizando-se um banco de DNA de pacientes deprimidos internados no Hospital de Pronto Socorro por tentativa de suicídio. Para o grupo controle, foram utilizados indivíduos sem diagnostico psiquiátrico, selecionados entre funcionários do Hospital de Clínicas de Porto Alegre. A análise molecular do receptor 5-HT1A foi realizada através da técnica de PCR-ARMS, e para o receptor 5-HT2A foi utilizada a técnica de PCR-RFLP. Os pacientes com pelo menos uma cópia do alelo G do receptor de serotonina 5-HT1A, apresentaram maior suscetibilidade à tentativa de suicídio do que os pacientes que não apresentaram o alelo G (P=0.029). Além disso, esse efeito foi associado com a amostra masculina (P=0.007). Os resultados dos testes para o receptor 5-HT2A indicaram uma associação do genótipo CC com o grupo controle (P= 0,046). Os testes para verificar a influencia desse polimorfismo em relação ao gênero também não foram significativos (P=0,224 e P=0,183). Baseado nos resultados pode-se corroborar a hipótese de que, para os receptores 5-HT1A, a presença do alelo G pode influenciar a atividade serotoninérgica nos homens. Assim, o alelo G torna-se um possível fator de suscetibilidade para o sexo masculino, somando as condições biológicas, ambientais e comportamentais, podendo resultar em uma maior vulnerabilidade ao comportamento suicida. Para os receptores 5-HT2A, os resultados não foram significativos, indicando que a presença do alelo polimórfico C não oferece suscetibilidade para essa amostra de pacientes depressivos com tentativa de suicídio. / This research aims to show that the involvement of specific polymorphisms may promote or provide an increased vulnerability to certain individuals who, when subjected to specific conditions of stress, may have suicide attempts. In recent years, the number of scientific papers showing that the brain of suicide victims present a change in serotonin receptors is growing. This research aimed to check the polymorphisms frequency of serotonin receptors 5-HT1A and 5-HT2A in depressive patients with suicide attempts and in a control group without psychiatric disease. The study was conducted using a DNA bank of depressive patients hospitalized in Hospital de Pronto Socorro for attempted suicide. The control group, consisted of individuals without psychiatric diagnosis, selected from employees of Hospital de Clínicas de Porto Alegre. The molecular analysis of 5-HT1A receptor was performed using the PCR-ARMS technique, and the 5-HT2A receptor was performed using the PCR-RFLP technique. Patients with at least one copy of G allele of serotonin receptor 5-HT1A, showed increased susceptibility to suicide attempts compared to patients who did not have the G allele (P=0.029). Moreover, this effect was associated with men (P=0.007). The results for the 5-HT2A receptor indicates an association of CC genotype with the control group (P= 0,046). The tests to check the influence of this polymorphism in relation to gender were not significant (P=0,224 and P=0,183). Based on these results we can corroborate the hypothesis that, for the 5-HT1A receptors the G allele may influence serotoninergic activity in men, by decreasing the transcription of 5-HT1A receptors. Therefore, the G allele becomes a possible susceptibility factor for males that, with the addition of biological, environmental and behavioral conditions, may result in an increased vulnerability to suicidal behavior. For the 5-HT2A receptors, the results were not significant, indicating that the presence of the polymorphic C allele does not provide susceptibility for this sample of depressive patients with suicide attempt.

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60 % inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic–pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

Chez un patient épileptique, aucun examen ne permet la délimitation exacte de la zone épileptogène (ZE) qui est définie par la zone corticale nécessaire à la genèse des crises. Dans les épilepsies du lobe temporal (ELT), près d'un tiers des patients ne sont pas libres de crises après la chirurgie en dépit d'un bilan préopératoire concluant. La tomographie par émission de positons (TEP) au [18F]MPPF permet la mise en évidence de zones d'hypofixation qui sont, à l'échelle du groupe, corrélées à l'épileptogénicité du parenchyme cérébral. Afin d'évaluer la validité de la TEP au [18F]MPPF pour identifier la ZE au plan individuel, tout d'abord nous avons comparé l'analyse visuelle et statistique par SPM de la TEP au [18F]FDG à la TEP au [18F]MPPF en termes de sensibilité et de spécificité chez 42 patients souffrant d'une ELT en cours de bilan préchirurgical. Dans une seconde étude nous avons développé une méthode d'analyse statistique d'un index d'asymétrie (IA) de la fixation du [18F]MPPF [BPND] et comparé les rendements de cette nouvelle approche à l'analyse standard SPM des images TEP en utilisant deux seuils statistiques différents (p< 0,05, corrigé au niveau du voxel et p< 0,05, corrigé au niveau du cluster) chez 24 patients opérés et guéris de leur ELT. Dans une troisième étude nous avons évalué, au niveau du groupe, l'influence d'un état dépressif sur le BPND du [18F]MPPF chez 24 patients souffrant d'une ELT. Ces trois études ont permis les conclusions suivantes : i) dans des conditions d'analyse identiques, La TEP au [18F]MPPF est supérieure au [18F]FDG pour identifier le lobe épileptogène chez des patients souffrant d'une ELT, ii) L'analyse de l'IA, avec un seuil à p< 0,05 corrigé au niveau du cluster, est la meilleure technique d'analyse de la TEP au [18F]MPPF et permet l'identification de la ZE avec une sensibilité de 96% et une spécificité de 88% dans l'ELT, iii) A l'échelle du groupe, un état dépressif est responsable d'une augmentation du BPND du [18F]MPPF dans les noyaux du raphé et l'insula controlatérale à la ZE.

The mechanisms that govern the repression of 5-HT1A receptor gene expression mediated by a novel mental retardation gene, Freud-1, were examined in HEK293 and SKNSH cells. This study provides a possible mechanism of 5-HT1A receptor gene regulation by Freud-1, which, to mediate its action, recruits Swi/Snf and Sin3A/histone deacetylase (HDAC) complexes in non-neuronal HEK293 cells and Swi/Snf only in neuronal, 5-HT1A receptor-expressing SKNSH cells. Thus, Freud-1 has a dual mechanism of repression depending on cell type: HDAC dependent in HEK293 cells and HDAC independent in SKNSH cells. In addition, I present evidence that Freud-1 is not sumoylated at its consensus sumoylation sites and I present the lipid binding properties of Freud-1 and Freud-1 mutants.

The mechanisms that govern the repression of 5-HT1A receptor gene expression mediated by a novel mental retardation gene, Freud-1, were examined in HEK293 and SKNSH cells. This study provides a possible mechanism of 5-HT1A receptor gene regulation by Freud-1, which, to mediate its action, recruits Swi/Snf and Sin3A/histone deacetylase (HDAC) complexes in non-neuronal HEK293 cells and Swi/Snf only in neuronal, 5-HT1A receptor-expressing SKNSH cells. Thus, Freud-1 has a dual mechanism of repression depending on cell type: HDAC dependent in HEK293 cells and HDAC independent in SKNSH cells. In addition, I present evidence that Freud-1 is not sumoylated at its consensus sumoylation sites and I present the lipid binding properties of Freud-1 and Freud-1 mutants.

Le système sérotoninergique, impliqué dans plusieurs pathologies du système nerveux central, peut être exploré in vivo par l'imagerie TEP (tomographie par émission de positons). La recherche et la validation préclinique de radiotraceurs ciblant spécifiquement les récepteurs sérotoninergiques est donc cruciale. Au cours de ce travail, nous nous sommes intéressés à deux récepteurs sérotoninergiques pour lesquels nous avons développé des outils moléculaires pour leur imagerie fonctionnelle: (i) les récepteurs 5-HT1A et (ii) les récepteurs 5-HT7. (i) Les récepteurs 5-HT1A sont parmi les récepteurs à sérotonine les mieux décrits à l'heure actuelle. Cependant, si des radiotraceurs TEP sont déjà disponibles, ceux-ci sont des antagonistes qui se fixent indifféremment aux récepteurs 5-HT1A, couplés aux protéines G et fonctionnels, et aux récepteurs 5-HT1A, découplés et non fonctionnels. Nous avons donc proposé une stratégie originale de développement d'un agoniste 5- HT1A radiomarqué au fluor afin d'accéder à une imagerie des récepteurs fonctionnels. Deux molécules, le F15599 et le F13714, initialement développées pour leurs propriétés antidépressives par un partenaire industriel, ont été radiomarquées au fluor 18 puis ont été évaluées in vitro, ex vivo et in vivo chez le rat et le chat. Nos résultats montrent que le [18F]F13714 permet de visualiser de manière inédite les récepteurs 5- HT1A couplés aux protéines G. (ii) Le deuxième axe de cette thèse concerne les récepteurs 5-HT7, de découverte récente et proposés comme cible thérapeutique antidépressive. A l'inverse des récepteurs 5-HT1A, les récepteurs 5-HT7 ne disposent pas encore de radiotraceur TEP. Notre approche a consisté à sélectionner, à partir du pharmacophore du récepteur, quatre structures d'antagonistes 5-HT7, synthétisées par un laboratoire partenaire de chimie : le 2FP3, le 4FP3, le 2FPMP et le 4FPMP. Nos études radiopharmacologiques in vitro, ex vivo et in vivo nous ont conduit à retenir un radiotraceur, le [18F]2FP3. À l'issue de ce travail de thèse CIFRE, nous pouvons donc proposer deux radiotraceurs TEP originaux, ouvrant des perspectives inédites d'imagerie moléculaires de la neurotransmission 5-HT1A et 5-HT7 et dont nous envisageons la poursuite du développement comme radiopharmaceutiques cliniques

The mechanisms that govern the repression of 5-HT1A receptor gene expression mediated by a novel mental retardation gene, Freud-1, were examined in HEK293 and SKNSH cells. This study provides a possible mechanism of 5-HT1A receptor gene regulation by Freud-1, which, to mediate its action, recruits Swi/Snf and Sin3A/histone deacetylase (HDAC) complexes in non-neuronal HEK293 cells and Swi/Snf only in neuronal, 5-HT1A receptor-expressing SKNSH cells. Thus, Freud-1 has a dual mechanism of repression depending on cell type: HDAC dependent in HEK293 cells and HDAC independent in SKNSH cells. In addition, I present evidence that Freud-1 is not sumoylated at its consensus sumoylation sites and I present the lipid binding properties of Freud-1 and Freud-1 mutants.

A presente pesquisa pretende mostrar que a participação de polimorfismos específicos podem favorecer ou fornecer uma vulnerabilidade maior a determinados indivíduos que, quando submetidos a condições específicas de estresse, podem tentar o suicídio. Nos últimos anos, vem crescendo na literatura científica o número de estudos que demonstram que o cérebro de vítimas de suicídio apresenta uma alteração nos receptores de serotonina. Este estudo teve como objetivo verificar a frequência dos polimorfismos dos receptores de serotonina 5-HT1A e 5-HT2A, em pacientes deprimidos que tentaram o suicídio e em um grupo controle sem doença psiquiátrica. O trabalho foi desenvolvido utilizando-se um banco de DNA de pacientes deprimidos internados no Hospital de Pronto Socorro por tentativa de suicídio. Para o grupo controle, foram utilizados indivíduos sem diagnostico psiquiátrico, selecionados entre funcionários do Hospital de Clínicas de Porto Alegre. A análise molecular do receptor 5-HT1A foi realizada através da técnica de PCR-ARMS, e para o receptor 5-HT2A foi utilizada a técnica de PCR-RFLP. Os pacientes com pelo menos uma cópia do alelo G do receptor de serotonina 5-HT1A, apresentaram maior suscetibilidade à tentativa de suicídio do que os pacientes que não apresentaram o alelo G (P=0.029). Além disso, esse efeito foi associado com a amostra masculina (P=0.007). Os resultados dos testes para o receptor 5-HT2A indicaram uma associação do genótipo CC com o grupo controle (P= 0,046). Os testes para verificar a influencia desse polimorfismo em relação ao gênero também não foram significativos (P=0,224 e P=0,183). Baseado nos resultados pode-se corroborar a hipótese de que, para os receptores 5-HT1A, a presença do alelo G pode influenciar a atividade serotoninérgica nos homens. Assim, o alelo G torna-se um possível fator de suscetibilidade para o sexo masculino, somando as condições biológicas, ambientais e comportamentais, podendo resultar em uma maior vulnerabilidade ao comportamento suicida. Para os receptores 5-HT2A, os resultados não foram significativos, indicando que a presença do alelo polimórfico C não oferece suscetibilidade para essa amostra de pacientes depressivos com tentativa de suicídio. / This research aims to show that the involvement of specific polymorphisms may promote or provide an increased vulnerability to certain individuals who, when subjected to specific conditions of stress, may have suicide attempts. In recent years, the number of scientific papers showing that the brain of suicide victims present a change in serotonin receptors is growing. This research aimed to check the polymorphisms frequency of serotonin receptors 5-HT1A and 5-HT2A in depressive patients with suicide attempts and in a control group without psychiatric disease. The study was conducted using a DNA bank of depressive patients hospitalized in Hospital de Pronto Socorro for attempted suicide. The control group, consisted of individuals without psychiatric diagnosis, selected from employees of Hospital de Clínicas de Porto Alegre. The molecular analysis of 5-HT1A receptor was performed using the PCR-ARMS technique, and the 5-HT2A receptor was performed using the PCR-RFLP technique. Patients with at least one copy of G allele of serotonin receptor 5-HT1A, showed increased susceptibility to suicide attempts compared to patients who did not have the G allele (P=0.029). Moreover, this effect was associated with men (P=0.007). The results for the 5-HT2A receptor indicates an association of CC genotype with the control group (P= 0,046). The tests to check the influence of this polymorphism in relation to gender were not significant (P=0,224 and P=0,183). Based on these results we can corroborate the hypothesis that, for the 5-HT1A receptors the G allele may influence serotoninergic activity in men, by decreasing the transcription of 5-HT1A receptors. Therefore, the G allele becomes a possible susceptibility factor for males that, with the addition of biological, environmental and behavioral conditions, may result in an increased vulnerability to suicidal behavior. For the 5-HT2A receptors, the results were not significant, indicating that the presence of the polymorphic C allele does not provide susceptibility for this sample of depressive patients with suicide attempt.

A epilepsia é a segunda causa mais freqüente de doenças neurológicas em adultos. A maioria dos pacientes epilépticos apresenta epilepsia do lobo temporal (ELT), cuja zona epileptogênica está localizada no lobo temporal. Altas taxas de psicopatologias são observadas em pacientes com epilepsia, principalmente ELT, quando comparados com a população geral. Uma vez que o neurotransmissor serotonina (5-HT) contribui com o neurodesenvolvimento, funcionalidade e plasticidade do cérebro adulto, alterações na neurotransmissão serotoninérgica poderiam contribuir para a etiologia da epilepsia. Além disso, a disfunção na atividade serotoninérgica no cérebro poderia aumentar a susceptibilidade a psicopatologias nos pacientes com epilepsia. Nesta linha, estudos de PET demonstraram uma diminuição no potencial de ligação dos receptores de serotonina (5-HT1A) em pacientes com epilepsia do lobo temporal, sendo que esta diminuição parece ser mais proeminente em pacientes epilépticos com depressão. Assim, genes relacionados com a neurotransmissão serotoninérgica são importantes candidatos para estudos de associação com a epilepsia. No presente trabalho, nós avaliamos o impacto de polimorfismos no gene do transportador da serotonina (5-HTT) e no gene do receptor 5-HT1A na ELT e em suas comorbidades psiquiátricas. O gene do transportador da serotonina apresenta dois polimorfismos com consequências funcionais na sua expressão: uma inserção/deleção de 44 pares de base na região flanqueadora 5’ (5-HTTLPR), e um número variável de repetições em tandem (VNTR) no intron 2 (5-HTTVNTR). O gene codificador do receptor 5-HT1A contém um polimorfismo de troca única de base (SNP) na região promotora (C-1019G) que altera a expressão gênica. Foram incluídos neste estudo 175 pacientes com ELT, dos quais 155 tinham avaliação neuropsiquiátrica, e 155 controles saudáveis. Primeiramente foi avaliado o impacto dos polimorfismos 5HTTLPR, 5HTTVNTR e C- 1019G na epilepsia do lobo temporal. Analisando os genótipos do 5-HTTVNTR e 5- HTTLPR combinados pela atividade transcricional, os genótipos de baixa expressão gênica foram mais freqüentes nos pacientes com ELT que nos controles saudáveis (O.R.=3.24; 95% I.C.=1.08 a 9.73; p=0.036). Esta associação com genótipos de baixa atividade trascricional do 5-HTT poderia estar relacionada com alterações funcionais do sistema serotoninérgico, aumentando o risco para epilepsia. Entretanto, não foi encontrada associação entre o polimorfismo C-1019G e a ELT. Na segunda parte deste trabalho, nós avaliamos a influência destes polimorfismos nas comorbidades de doenças psiquiátricas, entre elas transtorno de humor e ansiedade, em pacientes com ELT. Não foi encontrada diferença significativa na frequência dos polimorfismos no gene do transportador da serotonina (5-HTT) entre pacientes com ou sem comorbidade psiquiátrica. Entretanto o polimorfismo C-1019G foi associado com transtorno de ansiedade nos pacientes com ELT. Baseado em nossos resultados, sugerimos que alterações em genes relacionados à serotonina, como 5-HTT e 5-HT1A, poderiam estar envolvidas na gênese da ELT e nas características clínicas desta doença. Além disso, nós acreditamos que estudos futuros realizados com essa metodologia serão importantes para o estabelecimento das bases genéticas envolvidas nas manifestações neuropsiquiátricas da epilepsia do lobo temporal. / Epilepsy is the second most frequent cause of neurological disorders in young adults. The majority of the patients suffer from temporal lobe epilepsy (TLE). Higher rates of psychopathology are observed in patients with epilepsy, especially in those with TLE. Since neurotransmitter serotonin (5-HT) contributes to neurodevelopment, functionality and plasticity of the adult brain, serotonin may contribute to the etiology of epilepsy. Moreover, the impairment of serotoninergic activity in the brain may enhance susceptibility to psychopathologies in patients with epilepsy. In this line, PET studies showed a decreased serotonin receptor 1A binding in TLE patients, and this alteration seems to be higher in epileptic patients with depression. In this study we evaluated the impact of serotonin transporter (5-HTT) gene and serotonin receptor 1A (5-HT1A) polymorphisms over TLE and its psychiatric comorbidities. The 5-HTT gene has two polymorphisms with functional consequences: a 44 base pairs insertion/deletion polymorphism in the 5’ flanking region of this gene (5-HTTLPR), and a variable number of tandem repeats in the intron 2 (5-HTTVNTR). The gene encoding serotonin receptor 1A contains a single nucleotide polymorphism (SNP) in the promoter region (C-1019G) that regulates gene expression. In this study, were included 165 TLE patients, 155of these had been evaluated for neuropsychiatric disease, and 110 health controls. We first evaluated the impact of 5HTTLPR, 5HTTVNTR and C-1019G in temporal lobe epilepsy. When 5-HTTVNTR and 5-HTTLPR genotypes were combined by transcriptional efficiency, the low expressing genotypes were more frequent in TLE patients than in healthy controls (O.R.=3.24; 95% I.C.=1.08 a 9.73; p=0.036). This could be related to functional alterations and outgrowth inhibition of the serotonin system, and subsequently enhance the risk to epilepsy in adulthood. However we did not find an association between C-1019G and TLE. In the second part of this work we evaluated the influence of these polymorphisms on the risk for psychiatric diseases in these patients, among them mood and anxiety disorder. There were no significant differences between genotypes frequencies of 5-HTT polymorphisms and presence of any psychiatry disease. However, the C-1019G polymorphism was associated with anxiety disorder in TLE patients. Based in our results, we suggest that alteration in serotonin related genes, such as 5-HTT and 5- HT1A, might be involved in the genesis of TLE and in clinical characteristics of this disease. Moreover we believe that further studies involving molecular methodologies will be important to establish the genetic bases involved in the neuropsychiatric manifestations of TLE.