title: Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay.
abstract: BACKGROUND
  Despite the strong association between epilepsy and psychiatric comorbidities, few biological substrates are currently described. We have previously reported neuropathological alterations in mesial temporal lobe epilepsy (MTLE) patients with major depression and psychosis that suggest a morphological and neurochemical basis for psychopathological symptoms. Neuroinflammatory-related structures and molecules might be part of the altered neurochemical milieu underlying the association between epilepsy and psychiatric comorbidities, and such features have not been previously investigated in humans.
  
  
  METHODS
  MTLE hippocampi of subjects without psychiatric history (MTLEW), MTLE + major depression (MTLE + D), and MTLE + interictal psychosis (MTLE + P) derived from epilepsy surgery and control necropsies were investigated for reactive astrocytes (glial fibrillary acidic protein (GFAP)), activated microglia (human leukocyte antigen, MHC class II (HLA-DR)), glial metallothionein-I/II (MT-I/II), and aquaporin 4 (AQP4) immunohistochemistry.
  
  
  RESULTS
  We found an increased GFAP immunoreactive area in the molecular layers, granule cell layer, and cornus ammonis region 2 (CA2) and cornus ammonis region 1 (CA1) of MTLEW and MTLE + P, respectively, compared to MTLE + D. HLA-DR immunoreactive area was higher in cornus ammonis region 3 (CA3) of MTLE + P, compared to MTLE + D and MTLEW, and in the hilus, when compared to MTLEW. MTLEW cases showed increased MT-I/II area in the granule cell layer and CA1, compared to MTLE + P, and in the parasubiculum, when compared to MTLE + D and MTLE + P. Differences between MTLE and control, such as astrogliosis, microgliosis, increased MT-I/II, and decreased perivascular AQP4 in the epileptogenic hippocampus, were in agreement to what is currently described in the literature.
  
  
  CONCLUSIONS
  Neuroinflammatory-related molecules in MTLE hippocampus show a distinct pattern of expression when patients present with a comorbid psychiatric diagnosis, similar to what is found in the pure forms of schizophrenia and major depression. Future studies focusing on inflammatory characteristics of MTLE with psychiatric comorbidities might help in the design of better therapeutic strategies.
authors.affiliation: Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo (USP), Av Bandeirantes 3900, CEP 14049-900, Ribeirao Preto, SP, Brazil. ludykandra@gmail.com.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirao Preto, Brazil. ludykandra@gmail.com.
authors.forename: Ludmyla
authors.initials: L
authors.lastname: Kandratavicius
authors.affiliation: Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo (USP), Av Bandeirantes 3900, CEP 14049-900, Ribeirao Preto, SP, Brazil. e.peixotosantos@gmail.com.
authors.forename: Jose Eduardo
authors.initials: JE
authors.lastname: Peixoto-Santos
authors.affiliation: Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo (USP), Av Bandeirantes 3900, CEP 14049-900, Ribeirao Preto, SP, Brazil. marianamonteiro85@gmail.com.
authors.forename: Mariana Raquel
authors.initials: MR
authors.lastname: Monteiro
authors.affiliation: Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo (USP), Av Bandeirantes 3900, CEP 14049-900, Ribeirao Preto, SP, Brazil. renatascandiuzzi@yahoo.com.br.
authors.forename: Renata Caldo
authors.initials: RC
authors.lastname: Scandiuzzi
authors.affiliation: Department of Surgery, Ribeirao Preto Medical School, USP, Ribeirao Preto, Brazil. carlotti@fmrp.usp.br.
authors.forename: Carlos Gilberto
authors.initials: CG
authors.lastname: Carlotti
authors.affiliation: Department of Surgery, Ribeirao Preto Medical School, USP, Ribeirao Preto, Brazil. assiratijamj@uol.com.br.
authors.forename: Joao Alberto
authors.initials: JA
authors.lastname: Assirati
authors.affiliation: Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo (USP), Av Bandeirantes 3900, CEP 14049-900, Ribeirao Preto, SP, Brazil. jhallak@fmrp.usp.br.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirao Preto, Brazil. jhallak@fmrp.usp.br.|National Institute of Science and Technology in Translational Medicine (INCT-TM - CNPq), Ribeirao Preto, Brazil. jhallak@fmrp.usp.br.
authors.forename: Jaime Eduardo
authors.initials: JE
authors.lastname: Hallak
authors.affiliation: Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo (USP), Av Bandeirantes 3900, CEP 14049-900, Ribeirao Preto, SP, Brazil. jpleite@fmrp.usp.br.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirao Preto, Brazil. jpleite@fmrp.usp.br.
authors.forename: Joao Pereira
authors.initials: JP
authors.lastname: Leite
mesh_terms: D000293:Adolescent; D051401:Aquaporin 4 / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D016207:Cytokines / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000453:epidemiology* / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000453:epidemiology* / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D011618:Psychotic Disorders / Q000453:epidemiology / Q000473:pathology; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D006684:HLA-DR Antigens