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

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 p75 NTR , TrkB, TrkA, and TrkC immunohistochemistry. Increased expression of p75 NTR , 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 p75 NTR expression associated with interictal psychosis, and increased TrkB in those with psychosis or major depression was also reported, although their p75 NTR /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.

Analysis of rare copy number variation in absence epilepsies

“…Other GOIs that were disrupted by rare CNVs in patients with AE include NTRK2 , a BDNF receptor that modulates excitatory transmission, synaptic plasticity, and hippocampal LTP and is required for epileptogenesis in animal models. 43 Patients with mesial temporal lobe epilepsy show altered NTRK2 expression, 44 and dysregulated NTRK2-BDNF signaling is implicated in several neurodevelopmental disorders, indicating its excellent candidacy for AE. The potassium channel interacting protein gene KCNIP4 , deleted in a patient with JAE, forms part of a negative feedback loop in the Wnt/β-catenin pathway that regulates neuronal development and is a candidate for attention-deficit/hyperactivity disorder.…”

Animal models of epilepsy: use and limitations

“…For instance, two recent studies with transgenic mice have provided direct evidence that the development of kindling requires the BDNF receptor tyrosine kinase B (TrkB) activation through a specific phospholipase signaling 71,74. Although the tyrosine kinase B presence requirement for epileptogenesis has been evaluated mostly in kindling models, we have recently shown in human mesial TLE that increased hippocampal tyrosine kinase B expression also has a prominent role in secondary generalized seizures in addition to increased seizure frequency and poor surgical outcome 75. Taken together, these findings point out the importance of combing the kindling approach with cutting-edge tools to delimit novel targets for the prevention of epileptogenesis and the treatment of pharmacoresistant epilepsies.…”

2014 Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

“…Data on BDNF or trkB in the hippocampus of patients after SE are lacking. In individuals with MTLE, increased BDNF expression and reduced neuronal trkB expression in the hippocampus have been described (22,26). The higher trkB hippocampal expression in patients with MTLE and depression or psychosis (26) may render this subpopulation an interesting target population.…”