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Gene therapy for epilepsy: resculpturing synaptic transmission with neuropeptides

Toft Sörensen, Andreas LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:94.
Abstract
Intractable seizures and lack of effective antiepileptic drugs (AED) are severe and common conditions affecting many patients with epilepsy. Thus, there is an urgent need to develop new therapies in epilepsy. The search for novel treatments has identified several neuropeptide systems as potential targets for future therapeutic interventions. The neuropeptide Y (NPY) may represent one such target, as it plays a key role in controlling excitability in the hippocampus by suppressing glutamatergic transmission. If manipulated, the NPY system may be capable of restoring the imbalance between excitation and inhibition occurring in the epileptic brain. Indeed, emerging evidence has established a proof-of-principle for viral vector-mediated... (More)
Intractable seizures and lack of effective antiepileptic drugs (AED) are severe and common conditions affecting many patients with epilepsy. Thus, there is an urgent need to develop new therapies in epilepsy. The search for novel treatments has identified several neuropeptide systems as potential targets for future therapeutic interventions. The neuropeptide Y (NPY) may represent one such target, as it plays a key role in controlling excitability in the hippocampus by suppressing glutamatergic transmission. If manipulated, the NPY system may be capable of restoring the imbalance between excitation and inhibition occurring in the epileptic brain. Indeed, emerging evidence has established a proof-of-principle for viral vector-mediated transfer of gene and expression of NPY in epileptogenic regions of the brain, providing effective suppression of both acute and chronic seizures in animal models of epilepsy. Therefore, NPY gene therapy strategies are currently under intense investigation and clinical trials are forthcoming. To implement an effective NPY gene therapy in patients, as well as to extend our general knowledge of how transgene NPY may act in the brain, the receptor subtypes mediating the antiepileptic action of NPY needs to be determined. Moreover, the mechanisms underlying the seizure-suppressant effects of transgene NPY are not well understood. Particularly, we need to know under which circumstances transgene NPY is released, and whether and how it acts on synaptic transmission within the area of viral vector transduction.

In this thesis, evidences are provided showing that NPY is mediating its antiepileptic effect through activation of both Y2 and Y5 receptors in the hippocampus, and predominately via Y5 receptors in extra-hippocampal areas. Moreover, in rats, hippocampal NPY gene therapy generates long-lasting and neuronal-specific overexpression of transgene NPY. This is not associated with alterations in basal synaptic transmission, probably due to minor constitutive release of transgene NPY. However, as transgene NPY is preferentially released during high frequency neuronal activity, acting as a volume transmitter, it interferes with neuronal activity-dependent processes, reflected by suppressed long-lasting synaptic plasticity in hippocampal synapses and delayed, but not impaired, hippocampal dependent learning capacity in naïve animals. This could be an unwanted adverse effect of transgene NPY, but since already existing impairment of long-term synaptic plasticity is not further exacerbated after electrical kindling-induced seizures, NPY gene therapy still remains a promising and novel antiepileptic treatment strategy. (Less)
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author
supervisor
opponent
  • Prof Heinemann, Uwe, Institute of Neurophysiology, Charité – Berlin Medical University, Berlin, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
LTP, synaptic plasticity, synaptic transmission, electrophysiology, Y5 receptor, Y2 receptor, neuropeptide Y (NPY), hippocampus, gene therapy, epilepsy, memory, activity-dependent release, volume transmission
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:94
pages
134 pages
publisher
Institutionen för kliniska vetenskaper, Lunds universitet
defense location
Segerfalksalen, Wallenberg Neurocentrum, Lund
defense date
2008-10-10 09:15
ISSN
1652-8220
ISBN
978-91-86059-47-7
language
English
LU publication?
yes
id
0cfe7aea-5676-42af-96a0-f4ad32495541 (old id 1237808)
date added to LUP
2008-09-19 14:00:20
date last changed
2017-09-19 14:58:17
@phdthesis{0cfe7aea-5676-42af-96a0-f4ad32495541,
  abstract     = {Intractable seizures and lack of effective antiepileptic drugs (AED) are severe and common conditions affecting many patients with epilepsy. Thus, there is an urgent need to develop new therapies in epilepsy. The search for novel treatments has identified several neuropeptide systems as potential targets for future therapeutic interventions. The neuropeptide Y (NPY) may represent one such target, as it plays a key role in controlling excitability in the hippocampus by suppressing glutamatergic transmission. If manipulated, the NPY system may be capable of restoring the imbalance between excitation and inhibition occurring in the epileptic brain. Indeed, emerging evidence has established a proof-of-principle for viral vector-mediated transfer of gene and expression of NPY in epileptogenic regions of the brain, providing effective suppression of both acute and chronic seizures in animal models of epilepsy. Therefore, NPY gene therapy strategies are currently under intense investigation and clinical trials are forthcoming. To implement an effective NPY gene therapy in patients, as well as to extend our general knowledge of how transgene NPY may act in the brain, the receptor subtypes mediating the antiepileptic action of NPY needs to be determined. Moreover, the mechanisms underlying the seizure-suppressant effects of transgene NPY are not well understood. Particularly, we need to know under which circumstances transgene NPY is released, and whether and how it acts on synaptic transmission within the area of viral vector transduction.<br/><br>
	In this thesis, evidences are provided showing that NPY is mediating its antiepileptic effect through activation of both Y2 and Y5 receptors in the hippocampus, and predominately via Y5 receptors in extra-hippocampal areas. Moreover, in rats, hippocampal NPY gene therapy generates long-lasting and neuronal-specific overexpression of transgene NPY. This is not associated with alterations in basal synaptic transmission, probably due to minor constitutive release of transgene NPY. However, as transgene NPY is preferentially released during high frequency neuronal activity, acting as a volume transmitter, it interferes with neuronal activity-dependent processes, reflected by suppressed long-lasting synaptic plasticity in hippocampal synapses and delayed, but not impaired, hippocampal dependent learning capacity in naïve animals. This could be an unwanted adverse effect of transgene NPY, but since already existing impairment of long-term synaptic plasticity is not further exacerbated after electrical kindling-induced seizures, NPY gene therapy still remains a promising and novel antiepileptic treatment strategy.},
  author       = {Toft Sörensen, Andreas},
  isbn         = {978-91-86059-47-7},
  issn         = {1652-8220},
  keyword      = {LTP,synaptic plasticity,synaptic transmission,electrophysiology,Y5 receptor,Y2 receptor,neuropeptide Y (NPY),hippocampus,gene therapy,epilepsy,memory,activity-dependent release,volume transmission},
  language     = {eng},
  pages        = {134},
  publisher    = {Institutionen för kliniska vetenskaper, Lunds universitet},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Gene therapy for epilepsy: resculpturing synaptic transmission with neuropeptides},
  volume       = {2008:94},
  year         = {2008},
}