Clinical significance of altered kynurenine metabolism and
enhanced glutamatergic activity in MTLE-HS
As KYNA modulates the hippocampal extracellular glutamate release
through α7 nAChR (Carpenedo et al., 2001), it is possible that
exogenously applied KYNA prevented presynaptic action
potential-dependent glutamate release causing reduction in frequency of
spontaneous EPSCs recorded from pyramidal neurons in resected
hippocampal samples (Fig. 5E). As KYNA competitively inhibits
postsynaptic glycine binding site of the NMDA receptors and NMDA
receptor levels are high in patients with MTLE-HS, exogenous application
of KYNA may increase its binding to postsynaptic NMDA receptors causing
reduction in amplitude of spontaneous EPSCs (Figure 5e). In addition, we
also observed that the magnitude of reduction of frequency of
spontaneous EPSCs by KYNA in MTLE-HS was significantly less than that
caused by specific NMDA receptor antagonist, APV (Figure 5i). This might
suggests that, besides NMDA receptors, KYNA may have some other targets
like GPR35 (Alkondon et al., 2015), aryl hydrocarbon receptors (DiNatale
et al., 2010) or some other unknown sites; but their role in MTLE-HS is
not known and needs further investigations. Moreover, future experiments
involving comparison between KYNA and APV co-perfusion and KYNA or APV
alone can further help to understand the presence of a cumulative or
occlusive effect of these antagonists on NMDA receptor activity.
Increase in endogenous QUIN level in hippocampal samples also
contributes to glutamate receptor mediated hyperexcitability. QUIN binds
with postsynaptic NMDA receptors which are upregulated and render those
functionally hyperactive. It is tempting to speculate that decreased
KYNA levels as well as increased QUIN levels in the hippocampus and
hyperglutamatergic tone may contribute to seizure generation in patients
with MTLE-HS.
The primary limitation for this human study is use of tumour periphery
samples obtained from patients with low-grade gliomas as non-seizure
control, as ethically it was not possible to get healthy hippocampal
samples. The cell type variation, cell-specific expression pattern and
subtype differences of glutamate receptors between the MTLE-HS samples
and non-seizure control samples could also contribute to the changes
observed in the frequency and amplitude of spontaneous EPSCs. Although
previous studies have used samples obtained from non-MTLE patients for
comparison with MTLE-HS samples, we believe that epileptic samples
obtained from patients with non-MTLE (but DRE) could also have their own
limitations as “control” as those tissues will also possess, the
epilepsy related abnormalities which may significantly affect the
comparative results of synaptic transmission between the two groups. In
addition, it was not possible to obtain age and gender matched
non-seizure control specimens for this study. All the patients recruited
in this study were on a combination of anti-epileptic drugs
(supplementary table 1), so the effect of these drugs on
glutamatergic/GABAergic activity recorded from the pyramidal neurons of
resected hippocampal samples cannot be ruled out.