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Brain Inflammation and Adult Hippocampal Neurogenesis in Epilepsy

Chugh, Deepti LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:60.
Abstract
Epilepsy is a severe chronic neurological disorder characterized by recurrent spontaneous seizures. Excitatory/inhibitory (E/I) imbalance, neuronal loss, brain inflammation, and altered adult neurogenesis are some of the characteristic hallmarks of epilepsy. Seizures increase the production of new hippocampal neurons but their function in the epileptic brain is still not fully understood. Elucidating the mechanisms of how these newborn neurons integrate in the adult hippocampal circuitry could be important in understanding whether they contribute or counteract the pathology. Hence, one of the primary focuses of this thesis is to investigate the molecular modulators of synaptic integration of newborn neurons in seizure-induced pathological... (More)
Epilepsy is a severe chronic neurological disorder characterized by recurrent spontaneous seizures. Excitatory/inhibitory (E/I) imbalance, neuronal loss, brain inflammation, and altered adult neurogenesis are some of the characteristic hallmarks of epilepsy. Seizures increase the production of new hippocampal neurons but their function in the epileptic brain is still not fully understood. Elucidating the mechanisms of how these newborn neurons integrate in the adult hippocampal circuitry could be important in understanding whether they contribute or counteract the pathology. Hence, one of the primary focuses of this thesis is to investigate the molecular modulators of synaptic integration of newborn neurons in seizure-induced pathological environment (Paper 1). We show that the newborn neurons of 6 weeks of age exhibit a reduction in the expression of post-synaptic density-95 protein on dendritic spines with no changes in the expression of adhesion molecules neuroligin (NL)-1 and N-cadherin. Gephyrin, an inhibitory post-synaptic scaffolding protein was increased and adhesion molecule NL-2 was reduced at proximal dendrites. These findings suggest that newborn neurons of 6 weeks of age alter their afferent synaptic properties following status epilepticus (SE). Furthermore, we define a critical period during synaptic development of the newborn neurons when they are particularly sensitive to an inflammatory environment (Paper 2). We show that when new neurons encounter a lipopolysaccharide-induced inflammatory environment during early stages of synaptic development, they significantly change the expression pattern of both excitatory and inhibitory synaptic proteins.

Given the importance of inflammation in epilepsy, the role of a specific immune signaling mediated by the chemokine fractalkine and CX3CR1 was investigated with an objective to modulate the seizure-induced pathology (Paper 3). Intracerebroventricular infusion of anti-CX3CR1 antibody immediately following SE for one week diminished microglial cell activation, neuronal degeneration, and neuroblast production. These findings open up the possibility that fractalkine-CX3CR1 pathway may have anti-epileptogenic effects, which would be an interesting aspect to pursue in future studies. We also demonstrate the direct structural interactions between newly formed hippocampal neurons and microglia during synaptogenesis in a physiological and seizure-induced pathological environment using two-photon and confocal microscopy (Paper 4). We show that ramified microglia change their regional preferences with respect to their interactions with the newborn neurons following SE. Relatively more interactions were observed with the proximal dendrites known to receive primarily inhibitory synaptic inputs. Finally, the last study proposes a panel of molecular markers regulating the brain inflammation and the E/I balance in synapsin2 knockout mouse model of epileptogenesis, which could be further developed as potential biomarkers (Paper 5).

In conclusion, this thesis describes the role of brain inflammation in regulating synaptic integration of newborn neurons. Our results also suggest that blocking CX3CR1 after seizures could be a promising therapeutic approach. Furthermore, our findings concerning the molecular changes related to brain inflammation and E/I balance in a genetic mouse model of epileptogenesis could aid the development of biomarkers in future. (Less)
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author
supervisor
opponent
  • Prof. Gray, William P., Professor of Functional Neurosurgery, Neurosciences and Mental Health Research Institute, Cardiff University School of Medicine, Cardiff , United Kingdom
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Epilepsy, Inflammation, Neurogenesis, Hippocampus, Microglia, Adhesion molecules, Scaffolding proteins
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:60
pages
100 pages
publisher
Neurology, Lund
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund.
defense date
2015-05-18 13:00
ISSN
1652-8220
ISBN
978-91-7619-139-2
language
English
LU publication?
yes
id
56e4f4c8-b520-4ab8-aece-e8e4ac5e7928 (old id 5310906)
date added to LUP
2015-04-24 13:21:45
date last changed
2016-09-19 08:44:49
@phdthesis{56e4f4c8-b520-4ab8-aece-e8e4ac5e7928,
  abstract     = {Epilepsy is a severe chronic neurological disorder characterized by recurrent spontaneous seizures. Excitatory/inhibitory (E/I) imbalance, neuronal loss, brain inflammation, and altered adult neurogenesis are some of the characteristic hallmarks of epilepsy. Seizures increase the production of new hippocampal neurons but their function in the epileptic brain is still not fully understood. Elucidating the mechanisms of how these newborn neurons integrate in the adult hippocampal circuitry could be important in understanding whether they contribute or counteract the pathology. Hence, one of the primary focuses of this thesis is to investigate the molecular modulators of synaptic integration of newborn neurons in seizure-induced pathological environment (Paper 1). We show that the newborn neurons of 6 weeks of age exhibit a reduction in the expression of post-synaptic density-95 protein on dendritic spines with no changes in the expression of adhesion molecules neuroligin (NL)-1 and N-cadherin. Gephyrin, an inhibitory post-synaptic scaffolding protein was increased and adhesion molecule NL-2 was reduced at proximal dendrites. These findings suggest that newborn neurons of 6 weeks of age alter their afferent synaptic properties following status epilepticus (SE). Furthermore, we define a critical period during synaptic development of the newborn neurons when they are particularly sensitive to an inflammatory environment (Paper 2). We show that when new neurons encounter a lipopolysaccharide-induced inflammatory environment during early stages of synaptic development, they significantly change the expression pattern of both excitatory and inhibitory synaptic proteins. <br/><br>
Given the importance of inflammation in epilepsy, the role of a specific immune signaling mediated by the chemokine fractalkine and CX3CR1 was investigated with an objective to modulate the seizure-induced pathology (Paper 3). Intracerebroventricular infusion of anti-CX3CR1 antibody immediately following SE for one week diminished microglial cell activation, neuronal degeneration, and neuroblast production. These findings open up the possibility that fractalkine-CX3CR1 pathway may have anti-epileptogenic effects, which would be an interesting aspect to pursue in future studies. We also demonstrate the direct structural interactions between newly formed hippocampal neurons and microglia during synaptogenesis in a physiological and seizure-induced pathological environment using two-photon and confocal microscopy (Paper 4). We show that ramified microglia change their regional preferences with respect to their interactions with the newborn neurons following SE. Relatively more interactions were observed with the proximal dendrites known to receive primarily inhibitory synaptic inputs. Finally, the last study proposes a panel of molecular markers regulating the brain inflammation and the E/I balance in synapsin2 knockout mouse model of epileptogenesis, which could be further developed as potential biomarkers (Paper 5).<br/><br>
In conclusion, this thesis describes the role of brain inflammation in regulating synaptic integration of newborn neurons. Our results also suggest that blocking CX3CR1 after seizures could be a promising therapeutic approach. Furthermore, our findings concerning the molecular changes related to brain inflammation and E/I balance in a genetic mouse model of epileptogenesis could aid the development of biomarkers in future.},
  author       = {Chugh, Deepti},
  isbn         = {978-91-7619-139-2},
  issn         = {1652-8220},
  keyword      = {Epilepsy,Inflammation,Neurogenesis,Hippocampus,Microglia,Adhesion molecules,Scaffolding proteins},
  language     = {eng},
  pages        = {100},
  publisher    = {Neurology, Lund},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Brain Inflammation and Adult Hippocampal Neurogenesis in Epilepsy},
  volume       = {2015:60},
  year         = {2015},
}