| 1. |
- Hansen, Marita G., et al.
(författare)
-
Preserved function of afferent parvalbumin-positive perisomatic inhibitory synapses of dentate granule cells in rapidly kindled mice
- 2018
-
Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Parvalbumin- (PV-) containing basket cells constitute perisomatic GABAergic inhibitory interneurons innervating principal cells at perisomatic area, a strategic location that allows them to efficiently control the output and synchronize oscillatory activity at gamma frequency (30–90 Hz) oscillations. This oscillatory activity can convert into higher frequency epileptiform activity, and therefore could play an important role in the generation of seizures. However, the role of endogenous modulators of seizure activity, such as Neuropeptide Y (NPY), has not been fully explored in at PV input and output synapses. Here, using selective optogenetic activation of PV cells in the hippocampus, we show that seizures, induced by rapid kindling (RK) stimulations, enhance gamma-aminobutyric acid (GABA) release from PV cells onto dentate gyrus (DG) granule cells (GC). However, PV-GC synapses did not differ between controls and kindled animals in terms of GABA release probability, short-term plasticity and sensitivity to NPY. Kinetics of gamma-aminobutyric acid A (GABA-A) mediated currents in postsynaptic GC were also unaffected. When challenged by repetitive high-frequency optogenetic stimulations, PV synapses in kindled animals responded with enhanced GABA release onto GC. These results unveil a mechanism that might possibly contribute to the generation of abnormal synchrony and maintenance of epileptic seizures.
|
|
| 2. |
- Ledri, Marco, et al.
(författare)
-
Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus.
- 2015
-
Ingår i: The Journal of Neuroscience. - 1529-2401. ; 35:26, s. 9622-9631
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 3. |
- Sørensen, Andreas T., et al.
(författare)
-
Altered chloride homeostasis decreases the action potential threshold and increases hyperexcitability in hippocampal neurons
- 2017
-
Ingår i: eNeuro. - 2373-2822. ; 4:6
-
Tidskriftsartikel (refereegranskat)abstract
- Chloride ions play an important role in controlling excitability of principal neurons in the central nervous system. When neurotransmitter GABA is released from inhibitory interneurons, activated GABA type A (GABAA) receptors on principal neurons become permeable to chloride. Typically, chloride flows through activated GABAA receptors into the neurons causing hyperpolarization or shunting inhibition, and in turn inhibits action potential (AP) generation. However, in situations when intracellular chloride concentration is increased, chloride ions can flow in opposite direction, depolarize neurons, and promote AP generation. It is generally recognized that altered chloride homeostasis per se has no effect on the AP threshold. Here, we demonstrate that chloride overload of mouse principal CA3 pyramidal neurons not only makes these cells more excitable through GABAA receptor activation but also lowers the AP threshold, further aggravating excitability. This phenomenon has not been described in principal neurons and adds to our understanding of mechanisms regulating neuronal and network excitability, particularly in developing brain and during pathological situations with altered chloride homeostasis. This finding further broadens the spectrum of neuronal plasticity regulated by ionic compositions across the cellular membrane.
|
|
| 4. |
- Tönnesen, Jan, et al.
(författare)
-
Toward an Optogenetic Therapy for Epilepsy
- 2017
-
Ingår i: Optogenetics : From Neuronal Function to Mapping and Disease Biology - From Neuronal Function to Mapping and Disease Biology. - 9781107053014 ; , s. 292-307
-
Bokkapitel (refereegranskat)
|
|
| 5. |
- Wickham, Jenny, et al.
(författare)
-
Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients
- 2019
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- In epilepsy patients, drug-resistant seizures often originate in one of the temporal lobes. In selected cases, when certain requirements are met, this area is surgically resected for therapeutic reasons. We kept the resected tissue slices alive in vitro for 48 h to create a platform for testing a novel treatment strategy based on neuropeptide Y (NPY) against drug-resistant epilepsy. We demonstrate that NPY exerts a significant inhibitory effect on epileptiform activity, recorded with whole-cell patch-clamp, in human hippocampal dentate gyrus. Application of NPY reduced overall number of paroxysmal depolarising shifts and action potentials. This effect was mediated by Y2 receptors, since application of selective Y2-receptor antagonist blocked the effect of NPY. This proof-of-concept finding is an important translational milestone for validating NPY-based gene therapy for targeting focal drug-resistant epilepsies, and increasing the prospects for positive outcome in potential clinical trials.
|
|
