Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus

Abstract

Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene therapy is an evolving innovative approach that may prove useful for clinical applications. In animal models of temporal lobe epilepsy (TLE), gene therapy treatments based on viral vectors encoding NPY or galanin have been shown to effectively suppress seizures. However, how this translates to human TLE remains unknown. A unique possibility to validate these animal studies is provided by a surgical therapeutic approach, whereby resected epileptic tissue from temporal lobes of pharmacoresistant patients are available for neurophysiological studies in vitro. To test whether NPY and galanin have antiepileptic actions in human epileptic tissue as well, we applied these neuropeptides directly to human hippocampal slices in vitro. NPY strongly decreased stimulation-induced EPSPs in dentate gyrus and CA1 (up to 30 and 55%, respectively) via Y2 receptors, while galanin had no significant effect. Receptor autoradiographic binding revealed the presence of both NPY and galanin receptors, while functional receptor binding was only detected for NPY, suggesting that galanin receptor signaling may be impaired. These results underline the importance of validating findings from animal studies in human brain tissue, and advocate for NPY as a more appropriate candidate than galanin for future gene therapy trials in pharmacoresistant TLE patients.

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

“…), but neuropeptide Y was shown to suppress abnormal excitatory currents in human epileptic tissue (Ledri et al . ). In addition, disruption of adenosine and D‐serine signaling mechanisms associates with post‐synaptic molecular changes and lower seizure threshold (Klatte et al .…”

“…Indeed, neuropeptides and small molecule coagonists known to regulate network excitability and transmission tonus have been investigated for their potential to enhance seizure threshold, and gene therapy has been proposed as a treatment approach (Riban et al 2009). Among neuropeptides, brain-derived neurotrophic factor appears to promote epileptogenesis via TrkB activation (Liu et al 2013;Gu et al 2015), but neuropeptide Y was shown to suppress abnormal excitatory currents in human epileptic tissue (Ledri et al 2015). In addition, disruption of adenosine and D-serine signaling mechanisms associates with post-synaptic molecular changes and lower seizure threshold (Klatte et al 2013;Boison 2016).…”

The role of Neuropeptide Y in fear conditioning and extinction

“…Importantly, resected brain tissue taken from epileptic patients has provided evidence that NPY reduces excitatory transmission in the dentate gyrus and region CA1, via Y2 receptors, also in the human brain (Ledri et al, 2015;Patrylo et al, 1999). Furthermore, expression of NPY as well as Y1 and Y2 receptors undergo considerable plastic changes in the dentate gyrus and subiculum in animal models of epilepsy and in human tissue obtained by temporal lobe epilepsy surgery (Furtinger et al, 2001;Vezzani and Sperk, 2004).…”

Neuropeptide Y affects thalamic reticular nucleus neuronal firing and network synchronization associated with suppression of spike‐wave discharges

“…Of particular interest has been neuropeptide Y (NPY), which is widely and abundantly expressed in the mammalian central nervous system (CNS) and is a member of the pancreatic polypeptide family with 3 subtypes: Y1, Y2 and Y5. NPY is co‐localized with several other neurotransmitters and is a critical inhibitory regulator of neuronal excitability . A growing body of literature suggests that NPY plays an antiepileptic role in acquired focal epilepsy in patients as well as in animal models of acquired epilepsies…”

“…NPY is co-localized with several other neurotransmitters and is a critical inhibitory regulator of neuronal excitability. 5,6 A growing body of literature suggests that NPY plays an antiepileptic role in acquired focal epilepsy in patients 7,8 as well as in animal models of acquired epilepsies. 9,10 The seizures of GGEs, particularly absence seizures, involve pathologic oscillations of the cortico-thalamo-cortical circuit.…”