Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Comprehension of the complex mechanisms underlying epileptogenesis and seizure generation in temporal lobe epilepsy and other forms of epilepsy cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Some of these models replicate the natural history of symptomatic focal epilepsy with an initial epileptogenic insult, which is followed by an apparent latent period and by a subsequent period of chronic spontaneous seizures. Seizures are a combination of electrical and behavioral events that are able to induce chemical, molecular, and anatomic alterations. In this review, we summarize the most frequently used models of chronic epilepsy and models of acute seizures induced by chemoconvulsants, traumatic brain injury, and electrical or sound stimuli. Genetic models of absence seizures and models of seizures and status epilepticus in the immature brain were also examined. Major uses and limitations were highlighted, and neuropathological, behavioral, and neurophysiological similarities and differences between the model and the human equivalent were considered. The quest for seizure mechanisms can provide insights into overall brain functions and consciousness, and animal models of epilepsy will continue to promote the progress of both epilepsy and neurophysiology research.

Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

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. 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. 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. 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.

Metabotropic glutamate receptor type 5 (mGluR5) upregulation in temporal lobe epilepsy (TLE) and the correlation of its expression with features of hippocampal sclerosis (HS) remains unclear. Here we characterized mGluR5 immunoreactivity in hippocampus, entorhinal cortex (EC), and subiculum of TLE specimens with confirmed HS, with neocortical TLE (non‐HS) and necropsy controls. We correlated mGluR5 immunoreactivity with neuronal density, mossy fiber sprouting, astrogliosis (GFAP), and dendritic alterations (MAP2). TLE specimens showed increased mGluR5 expression, which was most pronounced in the EC, subiculum, CA2, and dentate gyrus outer molecular layer. Increased mGluR5 expression was seen in hippocampal head and body segments and was independent of neuronal density, astrogliosis, or dendritic alterations. Positive correlation between mGluR5 expression with mossy fiber sprouting and with MAP2 in CA3 and CA1 was found only in HS specimens. Negative correlation between mGluR5 expression with seizure frequency and epilepsy duration was found only in non‐HS cases. Specimens from HS patients without previous history of febrile seizure (FS) showed higher mGluR5 and MAP2 expression in CA2. Our study suggests that mGluR5 upregulation is part of a repertoire of post‐synaptic adaptations that might control overexcitation and excessive glutamate release rather than a dysfunction that leads to seizure facilitation. That would explain why non‐HS cases, on which seizures are likely to originate outside the hippocampal formation, also exhibit upregulated mGluR5. On the other hand, lower mGluR5 expression was related to increased seizure frequency. In addition to its role in hyperexcitability, mGluR5 upregulation could play a role in counterbalance mechanisms along the hyperexcitable circuitry uniquely altered in sclerotic hippocampal formation. Inefficient post‐synaptic compensatory morphological (dendritic branching) and glutamatergic (mGluR5 expression) mechanisms in CA2 subfield could potentially underlie the association of FS with HS and TLE. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

Summary: Objective: Hippocampal sclerosis is a common finding in patients with temporal lobe epilepsy (TLE), and magnetic resonance imaging (MRI) studies associate the reduction of hippocampal volume with the neuron loss seen on histologic evaluation. Astrogliosis and increased levels of chondroitin sulfate, a major component of brain extracellular matrix, are also seen in hippocampal sclerosis. Our aim was to evaluate the association between hippocampal volume and chondroitin sulfate, as well as neuronal and astroglial populations in the hippocampus of patients with TLE.Methods: Patients with drug‐resistant TLE were subdivided, according to hippocampal volume measured by MRI, into two groups: hippocampal atrophy (HA) or normal volume (NV) cases. Hippocampi from TLE patients and age‐matched controls were submitted to immunohistochemistry to evaluate neuronal population, astroglial population, and chondroitin sulfate expression with antibodies against neuron nuclei protein (NeuN), glial fibrillary acidic protein (GFAP), and chondroitin sulfate (CS‐56) antigens, respectively.Results: Both TLE groups were clinically similar. NV cases had higher hippocampal volume, both ipsilateral and contralateral, when compared to HA. Compared to controls, NV and HA patients had reduced neuron density, and increased GFAP and CS‐56 immunopositive area. There was no statistical difference between NV and HA groups in neuron density or immunopositive areas for GFAP and CS‐56. Hippocampal volume correlated positively with neuron density in CA1 and prosubiculum, and with immunopositive areas for CS‐56 in CA1, and negatively with immunopositive area for GFAP in CA1. Multiple linear regression analysis indicated that both neuron density and CS‐56 immunopositive area in CA1 were statistically significant predictors of hippocampal volume.Significance: Our findings indicate that neuron density and chondroitin sulfate immunopositive area in the CA1 subfield are crucial for the hippocampal volume, and that chondroitin sulfate is important for the maintenance of a normal hippocampal volume in some cases with severe neuron loss.