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

Abstract

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.

The p75 neurotrophin receptor: at the crossroad of neural repair and death

“…As recently reviewed (Ibanez and Simi, 2012;Kraemer et al, 2014;Meeker and Williams, 2014), increased neuronal expression of the p75 NTR has been documented in response to axotomy (Zhou et al, 1996;Johnson et al, 1999), neural damage, intraocular pressure (Wei et al, 2007), seizures (Roux et al, 1999;Ozbas-Gerceker et al, 2004) and ischemia (Kokaia et al, 1998). In addition to neurons, injury-induced increases in p75 NTR expression may occur in Schwann cells (Taniuchi et al, 1986;Gschwendtner et al, 2003;Zhou and Li, 2007;Provenzano et al, 2008), astrocytes (Choi and Friedman, 2009), oligodendrocytes (Beattie et al, 2002) or microglia/macrophages (Dowling et al, 1999;Wong et al, 2010).…”

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

“…In addition to neurons, the increases in p75 NTR may reflect expression in Schwann cells(Gai et al, 1996; Kobayashi et al, 2012; Richner et al, 2014), astrocytes(Cragnolini and Friedman, 2008; Cragnolini et al, 2009), oligodendrocytes(Dowling et al, 1999; Althaus and Richter-Landsberg, 2000; Casha et al, 2001; Beattie et al, 2002; Petratos et al, 2004; Guo et al, 2013) and microglia/macrophages(Dowling et al, 1999; Ozbas-Gerceker et al, 2004). …”

Neurotrophin receptors expression in mesial temporal lobe epilepsy with and without psychiatric comorbidities and their relation with seizure type and surgical outcome

“…Glial expression of p75 NTR was detected in MTLE groups, as already described in human MTLE [20] and in seizure models [65]. While in hippocampal neurons NGF binding to p75 NTR results in apoptosis [66], in glial cells the signal may serve as a negative modulator to restrict its proliferation [65].…”

“…Coexpression of p75 NTR and Trks has been previously demonstrated with immunofluorescence in hippocampal sclerosis [20], and a way to quantitatively express this relation is by examining p75 NTR and Trks expression ratios, as explored by Dwivedi et al [32]. Increased p75 NTR /Trks ratios in most hippocampal subfields of MTLE specimens Figure 4 TrkB expression in the human hippocampal formation.…”

“…NT receptors have been shown to play important roles in epileptogenesis, especially tyrosine receptor kinase B (TrkB) and p75 neurotrophic receptor (p75 NTR ) [17][18][19]. In human MTLE, a qualitative study performed in the dentate gyrus and Ammon's horn showed increased p75 NTR expression in glia and remaining neurons, and few alterations in Trk expression [20]. In animal models of epilepsy, increased NT receptors expression has also been related to increased excitability [21][22][23][24][25].…”