WO2021155866A1 - Préparation et application de modèle animal de dysplasie dendritique neuronale dans des régions cérébrales étendues - Google Patents

Préparation et application de modèle animal de dysplasie dendritique neuronale dans des régions cérébrales étendues Download PDF

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WO2021155866A1
WO2021155866A1 PCT/CN2021/075854 CN2021075854W WO2021155866A1 WO 2021155866 A1 WO2021155866 A1 WO 2021155866A1 CN 2021075854 W CN2021075854 W CN 2021075854W WO 2021155866 A1 WO2021155866 A1 WO 2021155866A1
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brain
dendritic
development
neuronal
neuron
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Chinese (zh)
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魏佑震
唐文洁
华一飞
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上海市东方医院（同济大学附属东方医院）
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/02—Breeding vertebrates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/35—Animals modified by environmental factors, e.g. temperature, O2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/106—Primate
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/107—Rabbit
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0318—Animal model for neurodegenerative disease, e.g. non- Alzheimer's

Definitions

  • the present invention relates to the field of biotechnology, in particular to the preparation and application of an animal model of neuronal dendritic development disorders in a wide range of brain regions.
  • H/I Hypoxic/ischemic injury is one of the main causes of brain dysfunction in all ages. It has been extensively studied in clinical and experimental animal studies, including etiology, neuropathogenesis and pharmacological intervention. More and more studies have shown that H/I may have an adverse effect on rodent brain development.
  • Blocking arterial blood vessels + hypoxia method-cerebral ischemia and hypoxia model Disadvantages: anesthesia has neuroprotective effect; surgery itself is traumatic; infarcts are highly variable and unstable; model making is troublesome and small in batches; success rate is low; The cycle is long.
  • Middle cerebral artery occlusion model This model is often used in adult rats, and it is only a cerebral ischemia or cerebral ischemia-reperfusion injury model without hypoxia; it is more suitable for clinical cerebral ischemia. A focal lesion model. It is not suitable for the simulation of neonatal hypoxic ischemic encephalopathy.
  • Clamping the trachea method the disadvantages are: anesthetic drugs have an impact on the nerves; the trauma caused by the operation itself; the technical requirements are high, the cycle is long; the batch size is small; because the mice used are generally older (too small, the operation is difficult), The consistency of pathological changes is poor.
  • hypoxic brain injury animal model which can be used as an animal model for studying the pathogenesis of neuronal dendritic development disorders in a wide range of brain regions and a powerful tool for screening new drugs.
  • the purpose of the present invention is to provide an animal model that can be used as a powerful tool for studying the pathogenesis of neuronal dendritic development disorders in a wide range of brain regions and for screening new drugs.
  • the first aspect of the present invention provides a method for preparing a non-human mammalian model of neuronal dendritic development disorders in a wide range of brain regions, including the following steps:
  • the oxygen concentration (volume ratio) drops from 10-20% to 1-5%.
  • the neuron dendritic development disorder of the extensive brain region includes the neuron dendritic spine development disorder of the extensive brain region.
  • the non-human mammals are rodents or primates, preferably including mice, rats, rabbits and/or monkeys.
  • the non-human mammal is a newborn non-human mammal, preferably, a newborn non-human mammal (such as a rodent) within 24 hours of birth or a newborn non-human mammal in the perinatal period. Mammals) such as primates).
  • an inert gas is added to reduce the oxygen concentration.
  • the inert gas is selected from the following group: nitrogen, helium, or a combination thereof.
  • the animal model of extensive brain neuron dendritic developmental disorder has one or more characteristics selected from the following group:
  • the synaptic physiological activity includes: mEPSCs amplitude and frequency.
  • the behavioral, emotional, and cognitive deficits include decreased spatial learning ability and memory ability, decreased active inquiry behavior, weaker fear of dangerous situations, and weaker natural fear of bright areas.
  • the second aspect of the present invention provides the use of a non-human mammalian model prepared by the method of the first aspect of the present invention, which is used as an animal model for studying neuronal dendritic development disorders in a wide range of brain regions.
  • the neuron dendritic development disorder of the extensive brain region includes the neuron dendritic spine development disorder of the extensive brain region.
  • the third aspect of the present invention provides a use of the non-human mammalian model prepared by the method of the first aspect of the present invention to screen or identify substances that can alleviate or treat neuronal dendritic development disorders in a wide range of brain regions (treatment Agent).
  • the neuron dendritic development disorder of the extensive brain region includes the neuron dendritic spine development disorder of the extensive brain region.
  • the fourth aspect of the present invention provides a method for screening or identifying potential therapeutic agents for treating or relieving neuronal dendritic development disorders in a wide range of brain regions, including the following steps:
  • test compound in the presence of the test compound, the test compound is applied to the non-human mammal model prepared by the method of the first aspect of the present invention, and the extensive brain area neurons of the animal model in the test group are detected
  • the test compound is a treatment or alleviation of widespread A potential therapeutic agent for neuronal dendritic development disorders in the brain area.
  • the detection of the severity of neuronal dendritic development disorders in a wide range of brain regions includes detecting changes in one or more indicators selected from the following group: synaptic electrophysiological activity; neuronal tree in each brain region The spine shape, size, number, distribution, and density of the spines and dendritic spines; the diameter, length, and number of the dendrites of neurons; the developmental status of the distribution of synapses and their constituent structures in each brain area; behavior, emotion, and cognition Function.
  • the reduction in the severity of the neuronal dendritic development disorder in the extensive brain area is manifested as: a decrease in the degree of decrease in the electrophysiological activity of the synapses; the spine density, size, number, The decrease in density is reduced; the diameter, length, and number of dendrites of neurons are reduced; the development of the distribution of synapses and their constituent structures in each brain area is reduced; and/or the degree of deficits in behavior, emotion, and cognitive functions is reduced.
  • the "significantly lower” means that the severity Q1 of the test group with biological duplication after administration of the test compound is lower than the severity Q2 of the control group with biological duplication after administration of the test compound, and After t test, the P value is less than 0.05.
  • the "significantly lower” means that the ratio of severity Q1/severity Q2 is ⁇ 1/2, preferably ⁇ 1/3, more preferably, ⁇ 1/4.
  • the method is non-diagnostic and non-therapeutic.
  • the method includes step (c), applying the potential therapeutic agent screened or identified in step (b) to the non-human mammal model prepared by the method of the first aspect of the present invention, thereby determining its effect on The animal model is widely affected by the severity of neuronal dendritic development disorders in the brain area.
  • the fifth aspect of the present invention provides a non-human mammal model, which is prepared by the method described in the first aspect of the present invention.
  • Figure 1 shows that this model animal did not cause significant changes after undergoing hypoxia. Among them, A: No change in the shape of the brain was found; B: No change in body weight was caused.
  • Figure 2 shows that the neuronal electrophysiological activities of the model rats are significantly affected after the hypoxic shock.
  • AC in vitro electrophysiology shows the decrease of synaptic electrical activity between brain neurons after hypoxia
  • DF in vivo electrophysiology shows changes in the electrophysiological function of the hippocampus with long-term depression (LYD) after hypoxia .
  • Figure 3 shows the brain light microscope observation after hypoxia, no significant changes were found in neuron morphology, size, arrangement, number, distribution, and density (A-J).
  • Figure 4 shows the brain light microscope observation after hypoxia, no significant changes were found in the morphology, size, arrangement, number, distribution, and density of microglia (A-F).
  • FIG 5 shows that the dendritic diameter, size, number, and density (B) of neurons in the hippocampus area of the hippocampus in the early stage (7 days after birth) after hypoxia are significantly reduced compared to normal mice (A); this difference is in More significant in adulthood (C, D)
  • Figure 6 shows other brain regions other than the hippocampus, such as the dentate gyrus (DG), the dendrites and dendritic spines of nerve cells have also seen hypoxia causing dendritic diameter reduction, dendritic length shortening, and dendritic spines Significant changes in density reduction (AF); in the CA3 area, the volume of the area composed of synapses composed of neuronal dendritic spines is reduced (GI).
  • DG dentate gyrus
  • GI neuronal dendritic spines
  • Figure 7 shows that the length of the dendrites emitted by neurons cultured in a hypoxic environment using in vitro cell culture methods decreased significantly, markedly on the first day (A, B), and the difference was even greater on the seventh day (C ,D).
  • Figure 8 shows the changes in the escape latency of the rats that have suffered hypoxia in the newborn period after adulthood, reflecting the significant decline in their spatial learning ability (A); the movement trajectory of the rats after being withdrawn from the platform (C) , Reflecting that its spatial memory ability is also significantly reduced (B, D).
  • Figure 10 shows Nissl staining of hippocampal CA1 area of rat brain tissue showing pyramidal neurons. After 35 minutes of hypoxia, the newborn rats survived reoxygenation and respiration for 3 days. The brain paraffin sections were taken for Nissl staining, showing neurons and glial cells. The results showed that after 3 days of hypoxia, there were no significant abnormalities in nerve cells compared with the normal control group. There is no manifestation of cellular edema.
  • the inventor unexpectedly discovered that exposure of non-human mammals to hypoxic conditions in which the oxygen concentration (volume ratio) is reduced from 10-20% to 1-5% for 30-40 minutes can be An animal model of neuronal dendritic development disorder in a wide range of brain regions is obtained.
  • the animal model of the present invention is an effective animal model of neuronal dendritic development disorder in a wide range of brain regions, which can be used to study the development of neuronal dendrites in a wide range of brain regions. Barriers, and can be used for screening and testing of specific drugs. The present invention has been completed on this basis.
  • the present invention establishes a relatively mild hypoxic condition (that is, mammals are exposed to a changing oxygen concentration environment, for example, the oxygen concentration (volume ratio) is reduced from 10-20% to 1-5% Under low oxygen conditions), significant neuron dendrites and their dendritic spines develop obstacles. Structural damage caused by such developmental obstacles persists, causing damage to learning, memory, and other cognitive behaviors.
  • a very effective non-human mammalian model of neuronal dendritic development disorders in a wide range of brain regions is provided.
  • non-human mammals include (but are not limited to): mice, rats, rabbits, monkeys, etc., more preferably rats and mice.
  • the animal model of the present invention is prepared by the following method:
  • the oxygen concentration (volume ratio) is reduced from 10-20% to 1-5%.
  • the animal model obtained by the method of the invention is fertile and develops normally.
  • a method for screening candidate drugs or therapeutic agents for the treatment of neuronal dendritic development disorders in a wide range of brain regions using the animal model of the present invention is also provided.
  • a candidate drug or therapeutic agent refers to a substance that is known to have a certain pharmacological activity or is being tested that may have a certain pharmacological activity, including but not limited to nucleic acids, proteins, chemically synthesized small molecules or large molecules. Molecular compounds, cells, etc.
  • the drug candidate or therapeutic agent can be administered orally, intravenously, intraperitoneally, subcutaneously, spinal canal, or direct intracerebral injection.
  • the intervention treatment factor is single. It was only given a condition of hypoxia, and no surgery or medication was performed on the animal body.
  • the model is uniform. Individual differences are small, the birth time of newborn rats is easy to grasp, and there is almost no external interference after birth.
  • the function of the damage point is critical.
  • the damage sites of the model are concentrated in the dendritic spines.
  • the dendritic spines are the key nodes in the connection of the neurons that make up the network of the brain. They are the main channels for the transmission of signals that affect each other between neurons, and are the signal transmission efficiency of the central nervous system network system.
  • the key point is the main structural basis for the level of brain function.
  • the animal model of the present invention is phenotypically stable.
  • the animal model obtained by the method of the present invention is fertile, and the general structure of the body is normally developed.
  • the animal model of the present invention can be used to study the role and mechanism of TSH in early brain neuron dendritic spines development.
  • the animal model of the present invention can be used to explore, develop, and verify potential drugs or methods and methods to interfere with TSH injury, block the developmental damage of dendritic spine, and improve the developmental obstacle of dendritic spine.
  • the animal model of the present invention can be used to study the functional changes of the nervous system and its operating mechanism under the pathological conditions of dendritic spines developmental disorders.
  • the animal model of the present invention is used as a reference for a nervous system model of mental retardation, for comparison and reference for learning and memory research under other neuropathological models (such as Alzheimer's disease).
  • the hypoxic condition of the present invention is hypoxia under normal pressure.
  • hypoxic conditions of the present invention have the characteristics of short duration and persistence.
  • Pregnant female rats are kept in an animal room with 12 hours of light and 12 hours of darkness. They have free access to food and water until they give birth.
  • the newborn rats were first placed in a hypoxic chamber with an oxygen concentration of 15%. Under the condition of 30°C, they were gradually adjusted to 3% by N2 within 30 minutes. After that, the oxygen concentration was maintained at 3%, and the newborn rats stayed in the box for another 5 minutes. Therefore, the total hypoxic injury lasted for 35 minutes, followed by normal breathing.
  • the normoxia treatment group newborn rats were placed in the box for 35 minutes, and the normoxia concentration was 21%.
  • hypoxia systemic reaction is obvious: at the end of the hypoxia treatment, the whole body color of the newborn rat is darker than the normal control group, and it recovers soon after the hypoxia treatment.
  • the brain morphology remains unchanged: The researchers also carefully compared the brains of young mice that were treated with TSH and normoxia within 5 days and 7 days, respectively. There was no significant difference in brain morphology and brain size between the hypoxia treatment group and the normoxia treatment group (Figure 1A).
  • TSH will not cause changes in the structure of brain nerve cells.
  • microglia are not activated. TSH does not induce brain activation of microglia. Observe the morphology, number, distribution, density, etc. of hippocampal CA1 microglia. Compared with normal ( Figure 4, A, B, C), the hippocampal microglia of hypoxic rats showed no obvious activation ( Figure 4). , D, E, F).
  • TSH causes the dendritic spine density of hippocampal neurons to decrease.
  • the structure details of the dendrites of hippocampal CA1 neurons, dendritic spines and granular cells in the DG of the brain area were detected respectively.
  • the dendritic spines of normal rat neurons are distributed in clusters along the dendrites.
  • the TSH of the dendritic spines of the animals is significantly reduced, sparsely distributed, and only a few are distributed along the dendrites (Figure 5).
  • the dendrites of neurons decrease in diameter.
  • the neuronal dendrites of hippocampal CA1 especially the secondary branches.
  • the average dendritic diameter of animals in the TSH group was roughly the same as that of the normal control group.
  • the diameter of the secondary branches of neuronal dendrites in TSH-treated animals was statistically smaller than that of the normoxic control group. Similar results were also observed 90 days after hypoxia and normoxia treatments ( Figure 5 and Table 2).
  • SH causes abnormal development of DG and CA3 regions.
  • the observation of the hippocampal dentate gyrus further confirmed that the density of dendritic spines in the hippocampus CA1 was reduced and the secondary branches of dendrites became thinner ( Figure 6A, 6B, 6C).
  • the dendritic spine density of DG granular cells in animals treated with TSH was 7.03 ⁇ 0.53/10um, which was lower than 14.8 ⁇ 0.60/10um in the normoxic control group, p ⁇ 0.0001 (Figure 6D).
  • the length of dendrites in the TSH group was significantly shorter than that in the control group.
  • the dendritic diameter of granular cells in the dentate gyrus of animals was 0.893 ⁇ 0.064m, which was significantly larger than 0.628 ⁇ 0.046m in the normal control group, p ⁇ 0.05 ( Figure 6E).
  • the dendritic contraction length of the inner molecular layer (IML) granular cells in the hippocampus DG of animals 90 days after TSH treatment was 15.35 ⁇ 1.75m, which was significantly higher than 7.04 ⁇ 1.02m in the normoxic control group, p ⁇ 0.001 ( Figure 6F).
  • TSH can cause long-term cognitive deficits.
  • Morris water maze experiment was performed on rats treated with TSH and normoxia at 3 months old.
  • rats in the control group and the hypoxia group showed similar improvements in the first 6 training sessions, and the latency of all animals in finding a platform was shortened.
  • the latency of rats in the TSH group was 21.6 ⁇ 3.71, 16.6 ⁇ 1.79, 20.4 ⁇ 3.86, which were significantly longer than those of the control group 12.1 ⁇ 1.72, 7.99 ⁇ 1.03, 8.07 ⁇ 0.96, respectively (p ⁇ 0.05) (Figure 8A).
  • Neonatal hypoxia injury is usually thought to be caused by umbilical cord around the neck, unlined head and pelvis, birth incarceration, poor blood supply to the uterus, and neonatal asphyxia.
  • Perinatal hypoxic-ischemic brain injury causes higher mortality and chronic neurological morbidity in acute infants and children, and often sequelae symptoms.
  • the present invention finds for the first time that TSH causes significant pathological changes, including the thinning and shortening of the tree of the central nervous system neurons, the decrease of dendritic spine density, the decrease of synaptic structure, and the decrease of synaptic electrophysiological function; in addition, in animals suffering from TSH Impaired cognitive function was observed in.
  • the data of the present invention clearly shows that TSH can cause significant neurosynaptic and dendritic toxicity in the neonatal and adult stages. Therefore, the present invention provides a useful animal model that can be used to study the effects and mechanisms of sublethal hypoxia on early brain development, and to explore potential intervention drugs or methods.
  • the study of the present invention shows that 6 hours after birth, newborn rats are given short sublethal hypoxia for 35 minutes alone, which is different from the previous animal model used for hypoxia/ischemia research.
  • animals born 6 hours old are used.
  • the animals used are about one Sunday old, which is closer to the clinical situation (umbilical cord around the neck, birth incarceration, uterine malformation, etc.).
  • the shorter the time after birth the smaller the individual coefficient of variation of the animal after birth, and the better the uniformity of the nervous system among the animals.
  • a single-factor gradient hypoxia supply is the second difference between the current study and previous animal models using carotid artery occlusion and hypoxia (two factors).
  • TSH blocks the spontaneous synaptic activity of neurons. Background activity of electroencephalogram (EEG) is found in very early preterm infants and animals.
  • EEG electroencephalogram
  • TSH caused a decrease in the amplitude and frequency of mEPSCs in hippocampal CA1 neurons.
  • TSH has a negative effect on the development of neuronal dendrites.
  • the diameter of the animal's neuron dendrites is significantly reduced.
  • the total dendritic length of the primary cultured hippocampal neurons was also significantly lower than that of the normal control group.
  • TSH damage induces dendritic toxicity and affects the growth and development of neuronal dendrites. Insufficient energy supply caused by hypoxia may affect cytoskeletal dynamics including actin and microtubules. Actin and MT are the keys to conventional dendritic growth and development, and they are the targets of many molecular pathways that control the growth of neuronal dendrites. During the development of the brain, the structure of actin and MT cytoskeleton changes, resulting in neuronal processes. The present invention also found that TSH damage reduces the density and development of dendritic spines. More than 95% of excitatory synapses on these neurons occur on dendritic spines, and each spine head is usually connected to form a synapse.
  • dendritic spines are very important for brain function.
  • the development of dendritic spines is controlled by the oxygen sensor PHD2, targeting the actin cross-linking agent Filamin-A to regulate synaptic density and neuronal activity within the network.
  • Dendritic spines-associated Rap-specific GDP enzyme activator protein is a post-synaptic protein that forms a complex with postsynaptic density (PSD)-95, which is subject to N-methyl-D-aspartic acid.
  • NMDARs are involved in regulating the morphogenesis of dendritic spines.
  • dendritic spines reflect the strength of synapses. In different brain diseases, including neurodegenerative diseases and mental diseases, the strength of synapses is usually severely affected. Dendritic spines can undergo several types of transitions, from growth to collapse, from elongation to shortening, and the time span for them to undergo this dynamic morphological activity is very short. Changes in the number and morphology of dendritic spines not only occur under pathological conditions such as excitotoxicity, but also occur in response to normal central nervous system development, hormone fluctuations, and neural activity under physiological environments.

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Abstract

L'invention concerne un procédé de préparation d'un modèle mammalien non humain de dysplasie dendritique neuronale dans des régions cérébrales étendues comprenant les étapes suivantes consistant à : exposer un mammifère non humain à des conditions de faible teneur en oxygène pendant 30 à 40 min pour obtenir un modèle animal de dysplasie dendritique neuronale dans des régions cérébrales étendues. Dans des conditions de faible teneur en oxygène, la concentration en oxygène (rapport de volume) chute de 10-20 % à 1-5 %. Le modèle animal peut être appliqué à l'étude de la dysplasie dendritique neuronale dans des régions cérébrales étendues, et peut être appliqué aux tests de dépistage et d'essai de médicaments particuliers.
PCT/CN2021/075854 2020-02-07 2021-02-07 Préparation et application de modèle animal de dysplasie dendritique neuronale dans des régions cérébrales étendues WO2021155866A1 (fr)

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