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Assessment of Dendritic Arborization in the Dentate Gyrus of the Hippocampal Region in Mice
Published on: March 31, 2015
Dentate granule neuron apoptosis and glia activation in murine hippocampus induced by trimethyltin exposure
A Fiedorowicz1, I Figiel, B Kamińska
1Laboratory of Neurochemistry, Department of Neurophysiology, Nencki Institute of Experimental Biology, Pasteura 3 Street, 02-093, Warsaw, Poland.
Abstract:
We investigated the effect of trimethyltin (TMT), a well-known neurotoxicant, on murine hippocampal neurons and glial cells. Three days following intraperitoneal (i.p.) injection of TMT into 1-month-old Balb/c mice at a dose of 2.5 mg/kg body weight we detected damage of the dentate gyrus granular neurons. The dying cells displayed chromatin condensation and internucleosomal DNA fragmentation, which are the most characteristic features of apoptosis. To study, if prolyl oligopeptidase is engaged in neuronal apoptosis following TMT administration, we pretreated mice with the specific inhibitor--Fmoc-Pro-ProCN in doses of 5 and 10 mg/kg body weight (i.p. injection). Three days following injection we did not observe any attenuation of neurotoxic damage, regardless of inhibitor dose, indicating the lack of prolyl oligopeptidase contribution to neuronal injury caused by TMT. The neurodegeneration was associated with reactive astrogliosis in whole hippocampus, but particularly in injured dentate gyrus. The reactive astrocytes showed an increased nerve growth factor (NGF) expression in ventral as well as dorsal hippocampal parts. NGF immunoreactivity was also augmented in neurons of CA3/CA4 areas, which were almost totally spared after TMT intoxication. It suggested a role for this neurotrophin in protection of pyramidal cells from loss of connection between CA3/CA4 and dentate gyrus fields. The granule neurons' death was accompanied by increased histochemical staining with isolectin B4, a marker of microglia, in the region of neurodegeneration. The microglial cells displayed ramified and ameboid morphology, characteristic of their reactive forms. Activated microglia were the main source of interleukin 1beta (IL-1beta). It is possible that this cytokine may participate in neurodegeneration of granule cells. Alternatively, IL-1beta elaborated by microglia could play a role in increasing NGF expression, both in astroglia and in CA3/CA4 neurons.
Insights
Trimethyltin (TMT) causes neurodegeneration in mouse hippocampus, characterized by apoptosis. Inhibition of prolyl oligopeptidase did not prevent TMT-induced neuronal damage, suggesting it is not involved in this neurotoxic process.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Trimethyltin (TMT) is a known neurotoxicant that affects hippocampal neurons and glial cells.
- Apoptosis, characterized by chromatin condensation and DNA fragmentation, is a key feature of TMT-induced neuronal death.
Purpose of the Study:
- To investigate the role of prolyl oligopeptidase in TMT-induced neurodegeneration.
- To examine the involvement of glial cells, specifically astrocytes and microglia, in the neurotoxic process.
- To explore the potential protective role of nerve growth factor (NGF) in TMT intoxication.
Main Methods:
- Intraperitoneal injection of TMT (2.5 mg/kg) into 1-month-old Balb/c mice.
- Pretreatment with a prolyl oligopeptidase inhibitor (Fmoc-Pro-ProCN) at doses of 5 and 10 mg/kg.
- Histochemical staining for isolectin B4 (microglia marker) and immunohistochemistry for NGF.
- Assessment of neuronal apoptosis and glial cell activation (astrogliosis, microgliosis).
Main Results:
- TMT administration led to significant damage and apoptosis of dentate gyrus granular neurons.
- Prolyl oligopeptidase inhibition did not attenuate TMT-induced neurotoxicity.
- Reactive astrogliosis and increased NGF expression were observed in the hippocampus.
- Activated microglia, expressing interleukin-1beta (IL-1beta), were present in the neurodegeneration site.
- NGF expression was also elevated in CA3/CA4 neurons, which were largely spared.
Conclusions:
- Prolyl oligopeptidase does not appear to play a significant role in TMT-induced hippocampal neurodegeneration.
- TMT intoxication triggers reactive astrogliosis and microglial activation, with IL-1beta potentially mediating granule cell death.
- NGF may play a neuroprotective role for CA3/CA4 neurons, possibly influenced by microglial-derived IL-1beta.
