Abstract
BackgroundThe dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility.MethodsWe isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it.Results3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture.ConclusionOur results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.
Highlights
The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory
We have shown that restoring neurogenesis to normal levels in chronically epileptic animals using the antidepressant fluoxetine completely corrects spatial learning impairment [14], demonstrating that reduced neurogenesis is pharmacologically reversible, and suggesting that altered neurogenesis is a key mechanism underlying spatial learning impairment in mesial temporal lobe epilepsy
Using standardised and validated battery of neuropsychological tests, including Logical Memory I and II (LM I and LM II), Verbal Paired Associates I and II (VPA I and VPA II), the Rey Complex Figure Test (ROCF) and the Warrington Recognition Memory Test for Words (RMT-W), poor verbal and non-verbal memory impairment were observed in 8 and 7 patients, respectively (Table 1). Both the tissue microenvironment and endogenous precursor cells are preserved in hippocampal Three dimensional (3D) cultures from adult human brain Haematoxylin & eosin staining showed that within 21 Days in vitro (DIV), cells re-aggregated into a threedimensional (3D) tissue-like structure (Fig. 1A)
Summary
The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Neurogenesis is a restricted event in the adult human brain largely confined to the dentate gyri [1] where it supports certain forms of hippocampal dependent learning and memory [2,3,4]. We have shown that restoring neurogenesis to normal levels in chronically epileptic animals using the antidepressant fluoxetine completely corrects spatial learning impairment [14], demonstrating that reduced neurogenesis is pharmacologically reversible, and suggesting that altered neurogenesis is a key mechanism underlying spatial learning impairment in mesial temporal lobe epilepsy. The underlying mechanisms of the initiation, maintenance and potential reversibility of altered neurogenesis in chronic human temporal lobe epilepsy remain unknown
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