ABSTRACT
Medial ganglionic eminence (MGE) is one of the sources of inhibitory interneurons during development. Following transplantation in postnatal developing brain, MGE cells can increase local inhibition suggesting a possible protection to GABAergic dysfunction in brain disorders, such as epilepsy. Since it has been shown that MGE-derived cells harvested as neurospheres are able to suppress seizures, it might be important to investigate whether these protective effects would change in different seizure models. Here, we used pentylenetetrazole-(PTZ) and maximal electroshock (MES)-induced seizure models to test whether the transplantation of MGE cells would increase the threshold to trigger acute seizures. When transplanted into the neocortex (layers 3-4) of neonatal mice (postnatal days 3-4), MGE cells were able to survive and were mainly found in piriform cortex, fimbria, and ventricular wall regions. Additionally, the number of GFP+ cells found in the brains of mice induced with PTZ and MES differed significantly and suggests proliferation and larger survival rate of MGE-transplanted cells after PTZ, but not MES-induced seizures. Following transplantation, there was a reduction in the number of animals presenting mild and severe seizures induced by PTZ. Furthermore, MGE-cell transplantation was able to increase threshold to seizures induced by PTZ, but was not able to prevent seizure spread induced by MES.
Subject(s)
Disease Models, Animal , Electroshock/adverse effects , Median Eminence/transplantation , Neural Stem Cells/transplantation , Pentylenetetrazole/toxicity , Seizures/therapy , Acute Disease , Animals , Female , Hippocampus/physiopathology , Interneurons , Male , Median Eminence/cytology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neocortex/physiopathology , Pregnancy , Seizures/etiology , Seizures/physiopathologyABSTRACT
BACKGROUND: The GABAergic system plays an important role in modulating levels of anxiety. When transplanted into the brain, precursor cells from the medial ganglionic eminence (MGE) have the ability to differentiate into GABAergic interneurons and modify the inhibitory tone in the host brain. Currently, two methods have been reported for obtaining MGE precursor cells for transplantation: fresh and neurosphere dissociated cells. Here, we investigated the effects generated by transplantation of the two types of cell preparations on anxiety behavior in rats. RESULTS: We transplanted freshly dissociated or neurosphere dissociated cells into the neonate brain of male rats on postnatal (PN) day 2-3. At early adulthood (PN 62-63), transplanted animals were tested in the Elevated Plus Maze (EPM). To verify the differentiation and migration pattern of the transplanted cells in vitro and in vivo, we performed immunohistochemistry for GFP and several interneuron-specific markers: neuropeptide Y (NPY), parvalbumin (PV) and calretinin (CR). Cells from both types of preparations expressed these interneuronal markers. However, an anxiolytic effect on behavior in the EPM was observed in animals that received the MGE-derived freshly dissociated cells but not in those that received the neurosphere dissociated cells. CONCLUSION: Our results suggest a long-lasting anxiolytic effect of transplanted freshly dissociated cells that reinforces the inhibitory function of the GABAergic neuronal circuitry in the hippocampus related to anxiety-like behavior in rats.
Subject(s)
Anxiety/therapy , Cell Transplantation/methods , Embryonic Stem Cells/transplantation , Median Eminence/transplantation , Neural Stem Cells/transplantation , Animals , Animals, Newborn , Anxiety/physiopathology , Calbindin 2/metabolism , Cell Culture Techniques , Cell Movement/physiology , Cerebral Cortex/physiopathology , Embryonic Stem Cells/physiology , Exploratory Behavior/physiology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hippocampus/physiopathology , Interneurons/physiology , Male , Median Eminence/embryology , Median Eminence/physiology , Neural Stem Cells/physiology , Neurogenesis/physiology , Neuropeptide Y/metabolism , Parvalbumins/metabolism , Rats, Sprague-Dawley , Rats, TransgenicABSTRACT
PURPOSE: Diseases such as temporal lobe epilepsy, brain trauma and stroke can induce endothelial cell proliferation and angiogenesis in specific brain areas. During status epilepticus (SE), bone marrow-derived cells are able to infiltrate and proliferate, dramatically increasing at the site of injury. However, it is still unclear whether these cells directly participate in vascular changes induced by SE. METHOD: To investigate the possible role of bone marrow-derived cells in angiogenesis after seizures, we induced SE by pilocarpine injection in previously prepared chimeric mice. Mice were euthanized at 8h, 7d or 15d after SE onset. RESULTS: Our results indicated that SE modified hippocampal vascularization and induced angiogenesis. Further, bone marrow-derived GFP(+) cells penetrated through the parenchyma and participated in the formation of new vessels after SE. We detected bone marrow-derived cells closely associated with vessels in the hippocampus, increasing the density of blood vessels that had decreased immediately after pilocarpine-induced SE. CONCLUSION: We conclude that epileptic seizures directly affect vascularization in the hippocampus mediated by bone marrow-derived cells in a time-dependent manner.
