Temporal lobe epilepsy patients with severe hippocampal neuron loss but normal hippocampal volume: Extracellular matrix molecules are important for the maintenance of hippocampal volume

Abstract

SUMMARYObjective: 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.

Individual hippocampal subfield assessment indicates that matrix macromolecules and gliosis are key elements for the increased T2 relaxation time seen in temporal lobe epilepsy

“…CSPG is, along with hyaluronic acid, the main component of brain ECM . Studies have shown increased levels of CSPG in the hippocampus of TLE patients and animal models . In the present study, we saw increased chondroitin sulfate levels, evaluated as CS‐56 area fraction, in all hippocampal subfields but the granule cell layer.…”

“…In fact, the developmental increase of CSPG in the intermediate zone of human fetal brain is followed by an increase in T2 signal, and the degradation of CSPG reduces T2 signal intensity in cartilage . In TLE, we showed that CSPG levels were crucial for maintaining hippocampal volume . The present study indicates the importance of CSPG for the higher in vivo T2 relaxation seen in the hippocampus of TLE patients.…”

“…Gliosis is a common finding in the hippocampus of TLE patients . Our evaluation revealed increased astroglial reaction and activated microglia (measured as, respectively, GFAP and HLA‐DR area fractions) in all hippocampal subfields, and both glial cells correlated with the relaxation time.…”

Protective Effects of Cannabidiol against Seizures and Neuronal Death in a Rat Model of Mesial Temporal Lobe Epilepsy

“…Patients and an animal model of MTLE often present neurodegenerative damage in different brain areas (Araujo et al, 2006; Diniz et al, 2011; Kandratavicius et al, 2015; Peixoto-Santos et al, 2015; Wolf et al, 2016). In particular, severe loss of hilar interneurons and pyramidal neurons in CA3 and CA1 is commonly seen in the hippocampus of MTLE patients and animal models (Turski et al, 1983a; Leite et al, 1996; Covolan et al, 2000).…”

Decreased neuron loss and memory dysfunction in pilocarpine-treated rats pre-exposed to hypoxia

“…Mesial temporal lobe epilepsy (MTLE) is characterized by focal seizures originating in the temporal lobe (Berg et al, 2010) A common neuropathological feature of MTLE is hippocampal sclerosis, characterized by neuron loss in selective hippocampal subfields, widespread hippocampal gliosis, and aberrant mossy fiber sprouting in the molecular layer of the dentate gyrus (DG) (Sutula et al, 1989;Babb et al, 1991;McNamara, 1994;Mathern et al, 1996;Kandratavicius et al, 2015;Peixoto-Santos et al, 2015).…”