Synaptic Integration of Hippocampal Neurons Generated in the Adult Brain: Influence of a Pathological Environment

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The adult brain constantly produces new neurons from endogenous neural progenitor cells located in at least two

regions, the subgranular zone (SGZ) in dentate gyrus of the hippocampus, and the subventricular zone (SVZ). Major

efforts are underway to discover the functional significance of new neurons in the adult brain. Several studies have indicated a relationship exists between newborn hippocampal neurons and learning and memory, suggesting that the new

neurons have a physiological role within the established circuitry. Individual newborn hippocampal neurons develop

into functional dentate granule cells and integrate normally into the hippocampal circuitry. They develop electrophysiological properties that are indistinguishable from the granule cells that were formed during early development.

Adult neurogenesis may provide the possibility for neuronal replacement therapy. Several brain pathologies have

been shown increase or decrease the magnitude of neurogenesis in the dentate gyrus. However, we do not know how

the new neurons function when they are born in a pathological environment. This information is crucial for potential

neuronal repair strategies utilizing endogenous neural progenitor cells.

In this thesis, we used electrophysiological techniques to study the functional integration of new neurons born in a pathological environment. In the first study, we used an animal model of temporal lobe epilepsy, status epilepticus

(SE), characterized by abnormal seizure activity, cell death and inflammation. In the second study we caused inflammation by intrahippocampal administration of lipopolysaccharide (LPS), which induced a strong inflammatory response but no seizure activity or cell death. After the insult, the new cells were labeled with a retrovirus tagged with green

fluorescent protein (GFP), which incorporates into dividing cells and the protein is expressed throughout the cell body and processes.The new cells were identified in acute brain slices based on their GFP expression and subjected whole-cell patch-clamp recordings.

We found that after SE the synaptic properties of the newborn neurons were consistent with enhanced inhibition

and reduced excitation, indicating they may act to attenuate the hyperexcitability caused by epilepsy. After the LPS-induced inflammation, the new neurons also received enhanced inhibitory input. Our findings indicate that the environment in which new neurons are born dramatically influences their synaptic integration into the circuitry. The overall functional significance is not known, and further studies are warranted in order to understand underlying mechanisms. Such investigations may lead to potential neuronal replacement strategies harnessing endogenous neural progenitor cells.

Details

Authors
  • Katherine Jakubs
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • neuropsykologi, neurofysiologi, Neurologi, synaptic plasticity, GABA, glutamate, GFP, Neurology, neuropsychology, neurophysiology, hippocampus, dentate gyrus, neurogenesis, LPS, inflammation, epilepsy, SE, patch-clamp
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2007 May 24
Publisher
  • Neurology, Lund
Print ISBNs978-91-85559-68-8
Publication statusPublished - 2007
Publication categoryResearch

Bibliographic note

Defence details Date: 2007-05-24 Time: 09:15 Place: Segerfalksalen, Wallenberg Neurocentrum BMC A10, Sölvegatan 17 221 84 Lund External reviewer(s) Name: Schinder, Alejandro Title: Dr. Affiliation: Fundación Instituto Leloir, Buenos Aires, Argentina ---