Traumatic brain injury (TBI) is very common. It is estimated that there is one TBI every 29s in the United States, with 1.5 million TBI patients each year, of whom 230,000 are hospitalized and survive, 80,000 are discharged with varying degrees of TBI-related disability, and 50,000 die, making TBI the leading cause of death and disability under the age of 40, and 5.3 million Americans have TBI-related disability. TBI has been an important topic of research in the field of neurosurgery, with a variety of causes, pathological types, and clinical outcomes. Among them, posttraumatic epilepsy (PTE) is a common sequela of TBI. Although there has been considerable research on animal models of TBI in the field of TBI research for a long time, covering various aspects of pathogenesis, pathology, pathophysiology and rehabilitation, epilepsy has been less frequently addressed. Similarly, in the field of epilepsy research, there is a lack of studies about PTE using TBI animal models. Only in recent years have researchers in both fields begun to conduct studies on the epileptogenesis (epileptogenicity) of TBI across their respective fields. The author provides a review on this topic. In humans, PTE refers to recurrent spontaneous seizures that occur after 1 week of TBI. seizures) within 24 h after TBI. However, such definitions are not available in animal models. 2. The formation process of PTE is symptomatic epilepsy, and its formation process is divided into three stages: first, TBI causes acute brain damage, and then experiences a latent period, during which the brain gradually changes at the histological, cytological and molecular levels for the epileptogenic process, and then recurrent seizures occur. The epileptogenic phase is the gestation period of PTE, which is triggered by TBI and causes a series of molecular and cellular changes, including cell death, gliosis, neural regeneration, axonal and dendritic plasticity changes, extracellular matrix reorganization, and vascular proliferation, etc. However, no specific landmark changes of the epileptogenic process have been found, and the length of the epileptogenic process varies. Current research on epilepsy treatment has focused on seizure prevention or suppression. Research on how to stop the epileptogenic process from all causes is lacking. In humans, there is a lack of effective ways to directly conduct basic research on the epileptogenic process. 3. TBI animal model and epilepsy profile Epilepsy refers to the electrophysiological clinical syndrome caused by abnormal brain discharge, and its clinical seizures are characterized by spontaneity and recurrence. Therefore, the PTE model must be a recurrent spontaneous seizure after TBI. Based on this point, making a PTE model requires in vivo, not brain slices or cell cultures. Of course the value of ex vivo studies cannot be underestimated, e.g. ex vivo studies can provide certain information related to PTE that is not available in the in vivo situation. The experimental animal models used to trigger hyperexcitability each have different efficacy and clinical utility. Previous animal models were mostly created by administering metals such as aluminum, cobalt, or iron to the cortex, creating a focal point of progressively higher excitability. These TBI animal models better mimic the pathological features of human TBI such as cortical contusion, blood-brain barrier disruption, subcortical damage, and axonal injury. In the literature on trauma, there are six main categories of TBI animal models: focal, diffuse, mixed focal and diffuse, combined TBI injury, coma models, and repetitive concussion models. However, in TBI animal model studies, systematic studies about delayed recurrent spontaneous seizures have been performed only in the lateral fluid-percussion model of brain injury (FPI) [5,6]. 4. iron chloride model of epilepsy There is blood-brain barrier disruption and hemorrhage in TBI, and there are iron-containing heme and iron deposits in the neurofibrillary network (neuropil). The characteristic pathological changes of surgically resected cortical specimens and cortical epileptogenic foci in patients with intractable PTE are iron-containing heme deposits. Therefore, iron is thought to be an important mediator of PTE. Thus, a cortical injection of ferrous chloride has been used to produce an animal model of PTE. The method was to inject 5 μl of 100 mmol/L ferrous chloride or ferric chloride aqueous normal human solution into the sensorimotor cortex (1 or 2 mm subdural) of adult SD rats at a rate of 1 μl/min. spikes appeared 15-45 min after injection, and most rats developed ipsilateral arcuate spikes or spikes or focal spikes with persistent bursts at 24 h. Between 2 and 5 d, 96% of rats developed complex partial seizures. Between 2 and 5 d, 96% of the rats developed complex partial seizures with ipsilateral focal epileptic electrical activity, which was transmitted to the contralateral side. After 6 weeks, the histological changes were neuronal loss and the appearance of activated astrocytes and iron-containing phagocytes. Foci of iron deposition were surrounded by fibroblasts. The surviving pyramidal neurons in layer 5 stained positively for iron. Dendritic spines and branches were reduced, and crinkled eosinophilic neurons appeared in the hippocampus and cerebellar hemispheres bilaterally after 6 months. Antiepileptic drugs including phenobarbital, phenytoin sodium, carbamazepine, sodium valproate, clonidine and ethosuximide have inhibited spontaneous seizures in animal models of ferric chloride epilepsy. It is generally believed that cortical injection of ferrous chloride impairs the cortex similarly to the effect of iron released from hemoglobin during intracranial hemorrhage. Iron mediates oxygen radical reactions that cause lipid oxidation of neuronal membranes, which in turn leads to functional changes and focal seizures. Therefore, oxygen radical scavengers are used to prevent seizures. Most studies are based on the administration of iron prior to injection, which has an inhibitory effect on epileptic activity in the acute phase, but no long-term effect. The epilepsy model made by iron application is characterized by spontaneous recurrent seizures, but there are still differences compared with human PTE: (1) almost all animals develop seizures after iron application, whereas in humans, at most 53% develop seizures during TBI; (2) in the animal model, the latency period for the development of seizures is nearly 2 d. It is unlikely that there is significant neuronal loop reorganization in such a short period of time, whereas in In humans, the latency period is relatively longer, from months to years; (3) in rats, seizures are limited, while in humans, a considerable number of seizures are secondary generalized seizures; (4) in animals, seizures tend to subside automatically; (5) in animal models, pathological changes are mainly limited to the cortex, while in humans, after heavy TBI, subcortical neuronal degeneration and axonal damage in the thalamus and hippocampus Neuronal degeneration, axonal damage and axonal sprouting of surviving neurons are all related to epileptogenicity; (6) in human PTE, there may be other mechanisms besides iron as an epileptogenic substance. The cortical undercut model was used to simulate PTE caused by penetrating cortical injury. The dura and blood supply are left intact, and a 28-30 gauge needle is folded at a 90° angle 2 mm from the end and attached to a micromanipulator. The needle was punctured through the soft membrane 2 mm posterior to fontanelle and 2 mm adjacent to the sagittal suture, and the needle was turned 180° under the sixth layer of the cortex, elevated, and retracted to make a parsagittal incision through the cortex, transecting the cortex below. To create a cortical island, another cortical incision was made 0.5 mm posterior to bregma without turning the needle. When the rats were executed 1 to 2 weeks later, at least 1 brain section in all animals produced evoked epileptiform potentials, and nearly 1/3 of the animals showed spontaneous epileptiform electrical activity. There are no conclusive reports of spontaneous or evoked seizures, and there is a lack of long-range video EEG monitorability studies. Histological studies revealed degeneration of pyramidal cells in layer 5 of the cortex, axonal growth in other pyramidal cells, and axonal sprouting in surviving cells, causing a 56% increase in total axonal length, a 64% increase in the number of axonal side branches, and a doubling of the number of axonal swellings, with targets of sprouted axons including other pyramidal cells and inhibitory interneurons within layer 5 of the cortex. There was no significant change in the branching of pyramidal cell dendrites. Immunohistochemical studies showed an increase in glutamate decarboxylase-expressing cells and an increase in Parvalbum, calbindin-immunopositive neurons, which are γ-aminobutyric acid (GABA)-ergic inhibitory neurons. The inhibitory terminals terminating on layer 5 pyramidal cells were increased 2-fold in size and number. The anatomical basis of hyperexcitability in this model is thought to include dissociation of efferent and afferent axons of cortical layer 5 and 6 neurons, disruption of neural circuits within the cortex, and neuronal degeneration. Tetrodoxin, a sodium channel blocker, prevented hyperexcitability after application, but not after 11 d. In this model, the therapeutic window and mechanism of antiepileptic drugs for PTE were investigated. In this model, comparative studies with human cortical spike injuries regarding neuronal loop reorganization and other characteristics are difficult to perform because of the lack of information on humans. In human TBI, tears in the hippocampal umbrella-vault and white matter pathways can be present, but white matter cutting injuries are rare. Further studies are needed regarding the influence of inflammatory processes accompanying phagocytosis and microglia activation and long-term neuronal degenerative processes such as Warren’s degeneration on long-term outcomes. Whether the rapid onset of hyperexcitability of brain slices is associated with spontaneous seizures in most animals in this model needs to be investigated. 6. post-traumatic epilepsy after FPI In experimental studies of epilepsy, the epileptogenic process is mostly triggered by inducing status epilepticus (SE). fpi is the most commonly used animal model for studying closed brain injury in humans. It has been found that the pathological changes in the brain after FPI are similar to the histological changes triggered by SE. However, PTE after FPI has only recently been reported. 6.1 Adult rats FPI is epileptogenic in adult rats, causing spontaneous seizures [FPI animal models were made with the cranial center located 4.4 mm posterior to the anterior chimney and 3.6 mm lateral to the anterior chimney, with an impact pressure of 2.9 to 3.3 atmospheres, causing heavy brain damage. Video-EEG was used for monitoring for up to 11 months. At the end of the study, seizures were found in 50% of the rats, and the latency period from injury to seizure onset ranged from 6 weeks to 11 months. Based on the preliminary findings, it was estimated that 50% of the animals that would develop seizures after FPI developed spontaneous seizures 7 to 8 months after injury. The median behavioral seizure score was 4 on the Racine scale, and 78% had secondary generalized seizures. Intracranial recordings showed that electrical seizures were first recorded in the ventral hippocampus on the side of injury and then rapidly transmitted to the contralateral cortex. The median seizure frequency was 0.15 seizures/d (0.04 to 0.4 seizures/d), with 1 seizure nearly every 2 weeks. The median seizure duration was 85s (29s-196s) and 50% of the seizures occurred between 7am and 19pm. Histological analysis of coronal sections of the brain stained with sulfur cordial at 11 months after FPI revealed considerable neurological deficits in the hippocampus bilaterally, more so ipsilaterally, and neuronal damage in the hilar area, CA3 and CA1. Immunohistochemical studies showed degeneration of inhibitory neurons in the hilar area and loss of nearly 60% of excitatory mossy neurons innervating inhibitory neurons, which may be related to increased excitability of the dentate gyrus after FPI. However, Reeves et al. found increased GABA immunoreactivity in the granular and intramolecular layers 2 d and 15 d after FPI, which was associated with increased inhibition in the dentate gyrus. Immunohistochemical studies showed an increase in activated astrocytes at the site of brain injury in rats from several weeks to 1 year after moderate FPI, and Grady et al. found that microglia continued to increase in different subregions of the hippocampus and in the portal region of the dentate gyrus in rats 14 d after FPI. Therefore, as with other epileptogenic brain damage, FPI can cause cell proliferation in the cortex, dentate gyrus, and periventricular cells in rats. Rats that developed PTE after FPI had significant bilateral mossy fiber sprouting to focus on the injury, and the mechanism of mossy fiber sprouting may involve the TrkB-ERK 1/2 CCREB/Elk-1 signaling pathway, which is activated within 24 h after FPI. Golarai et al. found bilateral mossy fiber sprouting in a heavy drop brain injury model analyzed 2 to 15 weeks after brain injury. In addition to axonal changes, recent studies have shown that dendrites are remodeling in the first month after FPI in rats 19-20 d after birth. Other pathological changes that may be associated with epileptogenicity after brain injury include synaptic axonal damage and vascular changes. In mice, rats, and humans, there is persistent axonal damage in the major conduction pathways for weeks to months after brain injury. The remaining vascular endothelial cells after brain injury are dysfunctional, and there is damage to microvascular structures in the contusion area, the peri-contusion area, and sites away from the contusion focus, including the contralateral side, for up to 1 week. Secondary microthrombosis peaks 1 to 3 d after injury. There is no information available on studies of the epileptogenic effects of antiepileptic drugs or other treatments on FPI. Acute studies have shown that Topiramate, Remacemide, and Talampanel may reduce lateral fluid percussion-induced brain damage, but further studies are needed to prevent or reduce epileptogenicity. 6,2 Juvenile rats were studied in male SD pups at 30-32 d after birth and were given lateral fluid percussion trauma, but in a more anterior position, with a bone window of 3 mm, centered 2 mm behind bregma and 3 mm outside the midline. 83% of the rats developed spontaneous total 7-9 Hz spiking waves within 1 month, starting at the top of the frontal area. 92% of the rats developed partial seizures within 4 months. At 7 months of follow-up, the frequency of seizure-like episodes from the hippocampus increased, suggesting a shift in the origin of seizures from the frontoparietal cortex to the hippocampus. Nissler staining and glial fibrillary acidic protein staining studies showed that early pathological changes were limited to the area around the ipsilateral cortical injury and the hippocampus was not involved, but in the chronic phase, cortical and hippocampal atrophy occurred, probably due to prolonged seizures and antiepileptic drugs. Compared with adult rats, after FPI, young rats showed a high rate of hyperexcitability, a short duration of seizure-like episodes, and a short latency period from injury to the appearance of spontaneous seizures. This may be related to a variety of factors including age, injury device, degree of injury, anesthesia, and site. 7, Conclusion PTE is a common complication and sequelae of TBI, and the mechanism of its occurrence is still unclear and needs to be studied at the cellular and molecular levels with the help of animal models. There are several animal models of traumatic epilepsy, such as iron chloride epilepsy model and cortical undercut epilepsy model, but these traumatic epilepsy models only simulate human traumatic epilepsy in some aspects, which have great limitations for studying the epileptogenic process. In recent years, it has been observed that FPI can cause chronic epilepsy in animals, which has better analogy with human PTE, and can be used to study the process of PTE occurrence and development after TBI in humans at the cellular and molecular levels.