Dentate Granule Cell Neurogenesis Is Increased by Seizures and Contributes to Aberrant Network Reorganization in the Adult Rat Hippocampus

By J. Parent, T. Yu, Rebecca T. Leibowitz, Daniel H. Geschwind, R. S. Sloviter, D. Lowenstein. 1997

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-specific markers turned on after division, 64 kDa, class III β-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.

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Citations in the corpus

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “Strikingly, even a transient seizure, induced by pilocarpine (hours) (Parent et al., 1997) or electroconvulsion (minutes) (Ma et al., 2009), leads to sustained increases in precursor proliferation for days and weeks, indicating a form of memory in regulation of neurogenesis by neuronal activity.”
New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? (2010, background): “For example, a drug-induced seizure increases NPC proliferatio”
Granule-Like Neurons at the Hilar/CA3 Border after Status Epilepticus and Their Synchrony with Area CA3 Pyramidal Cells: Functional Implications of Seizure-Induced Neurogenesis (2000, background): “Of particular relevance to our hypothesis was a study by Parent et al. (1997), which used the mitotic marker bromodeoxyuridine (BrdU) to label newly born cells.”
Synchronization from Second Order Network Connectivity Statistics (2011, background): “In many diseases strong evidence suggests reorganization of the neuronal connections causing or caused by the disease (Cavazos et al., 1991; Parent et al., 1997; Zeng et al., 2007) may play a role in generating these pathological behaviors.”
Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways (2006, unknown): “, 1998 ; Parent et al .”
Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. (2007, background): “In some animal models of epilepsy (systemic pilocarpine or kainate injection), a transient stimulation of dentate neurogenesis has been reported (Parent et al., 1997; Scharfman et al., 2000; and others), but in these models, no granule cell dispersion occurs.”
Adult neurogenesis: from precursors to network and physiology. (2005, background): “The newly born cells induced by seizures, which survive for up to 4 wk and differentiate into neurons (430), migrate to abnormal locations such as the CA3 cell layer, the dentate hilus and inner molecular layer (108, 430, 487).”
Neurogenesis in the adult brain: new strategies for central nervous system diseases. (2004, background): “Aberrant migration and network reorganization, as well as altered physiological properties of the newly generated ectopic neurons, were demonstrated following seizure activity (104, 110, 113).”
Rat forebrain neurogenesis and striatal neuron replacement after focal stroke (2002, methodology): “Diaminobenzidine peroxidase immunohistochemistry was performed on free-floating sections as described previously.(29,30) To label proliferating cells, we used primary antibodies that recognize BrdU (mouse monoclonal; 1:1,000; Boehringer Mannheim) and cdc2 (mouse monoclonal; 1:1,000; Santa Cruz Biote”
Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus (2000, methodology): “The 4 d time point was chosen because a similar paradigm has been used in a previous study of chemical-induced seizures on hippocampal neurogenesis (Parent et al., 1997).”
Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. (2016, unknown): “Seizure activity increases adult neurogenesis but also results in aberrant migration, morphology, and connectivity of newborn cells (Parent et al., 1997).”
Development of neural stem cell in the adult brain. (2008, background): “Interestingly, a dramatic acceleration of neuronal development, such as after recurrent seizures [45] or knockdown of DISC1 [19 ], leads to aberrant incorporation of new neurons into the existing circuitry.”