Neurotrophin receptor immunoreactivity in the hippocampus of patients with mesial temporal lobe epilepsy

Department of Medical Biology, Hacettepe University, Ankara, Turkey.
Neuropathology and Applied Neurobiology (Impact Factor: 3.93). 12/2004; 30(6):651-64. DOI: 10.1111/j.1365-2990.2004.00582.x
Source: PubMed


Recent evidence supports a critical role of neurotrophins in the regulation of both neuronal survival and synaptic transmission during epileptogenesis. We have examined the immunohistochemical expression of high- (tyrosine kinase receptors, trk) and low-affinity (p75) neurotrophin receptors (NTRs) in the hippocampal specimens from 18 patients with chronic temporal lobe epilepsy [TLE; 14 patients with hippocampal sclerosis (HS) and four with focal lesions (tumours) not involving the hippocampus proper]. Nonepileptic autopsy brains (n = 6) and surgical specimens from tumour patients without epilepsy (n = 3) were used as controls. Immunoreactivity (IR) for the trk receptors (trkA, trkB, trkC) was detected in normal human brain within the pyramidal neurones of hippocampal cornus ammoni (CA) regions and in the dentate gyrus. There were no detectable differences in the neuronal trk IR patterns in the hippocampus between control and TLE cases with HS, except for a decrease in neuronal density in regions where cell death had occurred (CA1, CA3 and CA4). In contrast, a consistent increase in trkA IR was observed in reactive astrocytes in CA1 and dentate gyrus. The low-affinity p75 neurotrophin receptor (p75(NTR)) was expressed in low levels in postnatal normal hippocampus. In contrast, neuronal p75(NTR) IR was detected in 10/14 cases of HS in spared neurones within the CA and hilar regions of the hippocampus. Double labelling revealed that p75(NTR)-positive neurones also contain trk receptor IR. In six cases with prominent glial activation strong p75(NTR) IR was observed in microglial cells within the sclerotic hippocampus. The present results indicate that changes in NTR expression are still detectable in the hippocampus of patients with chronic TLE and involve both glial and neuronal cells. Reactive astrocytes were immunoreactive for trkA, whereas activated microglia cells were reactive for p75(NTR), suggesting different functions for specific NTRs in the development of reactive gliosis. Moreover, the increased expression of p75(NTR) in hippocampal neurones of TLE patients may critically influence the neuronal survival during the epileptogenic process.

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    • "The low affinity NT receptor p75NTR may have a pro-apoptotic role when acting without Trks and/or as a ligand for pro-NTs; and p75NTR may have an anti-apoptotic role, strengthening mature NT biding and signal transduction when forming a complex with Trks [58]. Coexpression of p75NTR and Trks has been previously demonstrated with immunofluorescence in hippocampal sclerosis [20], and a way to quantitatively express this relation is by examining p75NTR and Trks expression ratios, as explored by Dwivedi et al. [32]. Increased p75NTR/Trks ratios in most hippocampal subfields of MTLE specimens suggests mechanisms toward cell survival and enhancement of the efficacy of synaptic neurotransmission, but decreased p75NTR/TrkB ratios in MTLE with psychiatric comorbidities could be associated with structural abnormalities and reduced neuronal plasticity in these hippocampi. "
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    ABSTRACT: Epilepsy and psychiatric comorbidities are frequently associated, but their common biological substrate is unknown. We have previously reported altered structural elements and neurotrophins (NTs) expression in mesial temporal lobe epilepsy (MTLE) patients with psychiatric comorbidities. NTs receptors can regulate neurotransmission and promote neuroplasticity, being important candidates in the regulation and manifestation of psychopatological states and seizure-related events. MTLE hippocampi of subjects without psychiatric history, MTLE¿+¿major depression, MTLE¿+¿interictal psychosis derived from epilepsy surgery, and control necropsies were investigated for p75NTR, TrkB, TrkA, and TrkC immunohistochemistry. Increased expression of p75NTR, decreased TrkA, unaltered TrkC, and complex alterations involving TrkB expression were seen in MTLE groups. Increased TrkB expression in patients without complete seizure remission and in those with secondarily generalized seizures was seen. Decreased p75NTR expression associated with interictal psychosis, and increased TrkB in those with psychosis or major depression was also reported, although their p75NTR/TrkB ratios were lower than in MTLE without psychiatric comorbidities. Our results provide evidence of alterations in expression of NTs receptors in the epileptogenic hippocampus that are differentially modulated in presence of psychiatric comorbidities. As already explored in animal models, even in chronic human MTLE increased TrkB expression, among other NT receptors alterations, may play a major role in seizure type, frequency and surgery outcome.
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    • "Neuron loss and gliosis in the patients with epilepsy, especially in the recurrent or state epilepsy patients [6] [27]. They play a critical role in the genesis and progression of epilepsy. "
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