Abstract
BackgroundDespite 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.MethodsMTLE 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.ResultsWe 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.ConclusionsNeuroinflammatory-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.
Highlights
Despite the strong association between epilepsy and psychiatric comorbidities, few biological substrates are currently described
We have recently shown neuropathological alterations in the hippocampus of patients with epilepsy and the history of major depression or interictal psychosis, which may indicate that structural changes and neurochemical dysfunctions may underlie psychiatric symptoms in mesial temporal lobe epilepsy (MTLE) [8,9,10]
We hypothesized that expression of reactive astrocytes, activated microglia, glial MT-I/metallothionein I and II (II), and aquaporin 4 (AQP4) would be altered in the hippocampal formation of MTLE patients with major depression and interictal psychosis
Summary
Despite the strong association between epilepsy and psychiatric comorbidities, few biological substrates are currently described. We have recently shown neuropathological alterations in the hippocampus of patients with epilepsy and the history of major depression or interictal psychosis, which may indicate that structural changes and neurochemical dysfunctions may underlie psychiatric symptoms in MTLE [8,9,10]. Neuroinflammation-related abnormalities such as glial pathology, glutamate dysregulation, and bloodbrain-barrier dysfunction are found in epilepsy, and in schizophrenia and major depression [11] Glial proteins, such as metallothionein I and II (MT-I/II), are able to quench free zinc and modulate glutamatergic neurotransmission [12], and aquaporin 4 (AQP4), found in astrocytic endfeets, is a regulator of water homeostasis that majorly controls edema formation and tissue excitability [13,14]. We hypothesized that expression of reactive astrocytes, activated microglia, glial MT-I/II, and AQP4 would be altered in the hippocampal formation of MTLE patients with major depression and interictal psychosis
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