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Published on: June 12, 2018
Aberrant generation of dentate gyrus granule cells is associated with epileptic susceptibility in p53 conditional
Nuria Ruiz-Reig1, Georges Chehade1, Xavier Yerna2
1Laboratory of Developmental Neurobiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
Abstract:
Neuronal apoptosis is a mechanism used to clear the cells of oxidative stress or DNA damage and refine the final number of neurons for a functional neuronal circuit. The tumor suppressor protein p53 is a key regulator of the cell cycle and serves as a checkpoint for eliminating neurons with high DNA damage, hyperproliferative signals or cellular stress. During development, p53 is largely expressed in progenitor cells. In the adult brain, p53 expression is restricted to the neurogenic niches where it regulates cell proliferation and self-renewal. To investigate the functional consequences of p53 deletion in the cortex and hippocampus, we generated a conditional mutant mouse (p53-cKO) in which p53 is deleted from pallial progenitors and their derivatives. Surprisingly, we did not find any significant change in the number of neurons in the mutant cortex or CA region of the hippocampus compared with control mice. However, p53-cKO mice exhibit more proliferative cells in the subgranular zone of the dentate gyrus and more granule cells in the granular cell layer. Glutamatergic synapses in the CA3 region are more numerous in p53-cKO mice compared with control littermates, which correlates with overexcitability and higher epileptic susceptibility in the mutant mice.
Insights
Deleting the tumor suppressor protein p53 in mice did not alter neuron numbers but increased cell proliferation in the hippocampus. This resulted in more synapses, leading to heightened brain excitability and epilepsy susceptibility.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Neuronal apoptosis removes damaged cells, regulated by the tumor suppressor protein p53.
- p53 is crucial for cell cycle checkpoints, particularly in progenitor cells during development and in adult neurogenic niches.
- Its role in the adult cortex and hippocampus, especially concerning neuronal numbers and circuit function, requires further investigation.
Purpose of the Study:
- To investigate the functional role of p53 in the adult cortex and hippocampus by generating a conditional knockout mouse model.
- To assess the impact of p53 deletion on neuronal populations, cell proliferation, and synaptic organization.
Main Methods:
- Generation of a conditional p53 knockout (p53-cKO) mouse model by deleting p53 in pallial progenitors and their derivatives.
- Analysis of neuronal numbers in the cortex and hippocampus (CA regions).
- Assessment of cell proliferation in the subgranular zone and granule cell layer of the dentate gyrus.
- Quantification of glutamatergic synapses in the CA3 region.
Main Results:
- No significant change in overall neuron numbers in the cortex or hippocampus (CA regions) of p53-cKO mice.
- Increased cell proliferation observed in the subgranular zone of the dentate gyrus in p53-cKO mice.
- Elevated number of granule cells in the granular cell layer and more glutamatergic synapses in the CA3 region of p53-cKO mice.
- p53-cKO mice exhibited increased brain excitability and higher susceptibility to epilepsy.
Conclusions:
- Conditional deletion of p53 in the pallial progenitors and derivatives does not affect overall neuronal numbers in the cortex and hippocampus.
- Loss of p53 leads to increased neurogenesis in the dentate gyrus, enhanced synaptic connectivity, and consequently, heightened neuronal excitability and epilepsy risk.
- These findings highlight a novel role for p53 in regulating adult neurogenesis and circuit stability, with implications for neurological disorders.
