Schizophrenia, a profoundly impactful neuropsychiatric disorder, has been the subject of extensive research using animal models. However, certain important aspects remain understudied, including assumed long-term consequences of psychotic episodes on negative symptoms development and progression. Addressing these limitations, we proposed a novel animal model in male rats based on early postnatal immune activation triggered by lipopolysaccharide (LPS), serving as the predisposing factor (1st hit). As the 2nd hit, representing psychotic-like episodes, we implemented a multi-episodic co-treatment with dizocilpine (MK-801) and amphetamine (AMP), spanning multiple developmental periods. The animals were tested in two social behavioral assays in adolescence and adulthood to investigate whether a social deficit would arise. In addition, we evaluated the level of oxytocin (OT), a neuropeptide relevant to social behavior, in selected brain regions. In the social interaction test, when animals could freely interact in the open field and express their social behavioral profile entirely, social behavior decreased in adolescent experimental animals. In the social approach test in the Y maze, all animals, irrespective of treatment, preferred conspecific over an indifferent object and novel rat over a familiar rat. Further, the results revealed that the OT content in the hypothalamus increased with age. In the proposed model, social interaction in the open field was decreased in adolescent but not in adult rats, indicating that the pharmacological manipulations caused only transient age-dependent changes. The study was thus in certain aspects successful in creating a novel approach to model social deficit potentially relevant to schizophrenia; other findings require further investigation.

• Klíčová slova
• Animal model, Oxytocin, Schizophrenia, Social behavior, Two-hit model, negative symptom,
• Publikační typ
• časopisecké články MeSH

Starting from simple clinical statistics, the spectrum of methods used in epilepsy research in the Institute of Physiology of the Czechoslovak (now Czech) Academy of Sciences progressively increased. Professor Servít used electrophysiological methods for study of brain activity in lower vertebrates, neuropathology was focused on electronmicroscopic study of cortical epileptic focus and ion-sensitive microelectrodes were used for studies of cortical direct current potentials. Developmental studies used electrophysiological methods (activity and projection of cortical epileptic foci, EEG under the influence of convulsant drugs, hippocampal, thalamic and cortical electrical stimulation for induction of epileptic afterdischarges and postictal period). Extensive pharmacological studies used seizures elicited by convulsant drugs (at first pentylenetetrazol but also other GABA antagonists as well as agonists of glutamate receptors). Motor performance and behavior were also studied during brain maturation. The last but not least molecular biology was included into the spectrum of methods. Many original data were published making a background of position of our laboratory in the first line of laboratories interested in brain development.

• MeSH
• akademie a ústavy MeSH
• biomedicínský výzkum trendy   MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• epilepsie * patofyziologie   MeSH
• lidé MeSH
• mozek účinky léků   fyziologie   růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH

Status epilepticus (SE) is the most common neurologic emergency in children. Both clinical and laboratory studies have demonstrated that SE in early life can cause brain damage and permanent behavioral abnormalities, trigger epileptogenesis, and interfere with normal brain development. In experimental rodent models, the consequences of seizures are dependent upon age, the model used, and seizure duration. In studies involving neonatal and infantile animals, the model used, experimental design, conditions during the experiment, and manipulation of animals can significantly affect the course of the experiments as well as the results obtained. Standardization of laboratory approaches, harmonization of scientific methodology, and improvement in data collection can improve the comparability of data among laboratories.

• Klíčová slova
• animal models, comorbidites, immature rodent, status epilepticus,
• MeSH
• laboratorní zvířata MeSH
• modely nemocí na zvířatech MeSH
• mozek MeSH
• status epilepticus * MeSH
• záchvaty MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.

• Klíčová slova
• Animal model, Histology, MRI, Myelin development, Status Epilepticus, Temporal Lobe Epilepsy, Thalamocortical connectivity, White matter integrity,
• MeSH
• bílá hmota * diagnostické zobrazování   patologie   MeSH
• dospělí MeSH
• epilepsie temporálního laloku * patologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• myelinová pochva patologie   MeSH
• předškolní dítě MeSH
• status epilepticus * chemicky indukované   patologie   MeSH
• zobrazování difuzních tenzorů MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• předškolní dítě MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. METHODS: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). RESULTS: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). CONCLUSIONS: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

• Klíčová slova
• Autism spectrum disorders, Developmental status epilepticus, Everolimus, TSC, Tuberous sclerosis complex, mTOR,
• MeSH
• autistická porucha * MeSH
• haploinsuficience MeSH
• krysa rodu Rattus MeSH
• status epilepticus * MeSH
• TOR serin-threoninkinasy genetika   MeSH
• tuberin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mTOR protein, rat MeSH Prohlížeč
• TOR serin-threoninkinasy MeSH
• Tsc2 protein, rat MeSH Prohlížeč
• tuberin MeSH

Temporal lobe epilepsy (TLE) is a severe neurological disorder accompanied by recurrent spontaneous seizures. Although the knowledge of TLE onset is still incomplete, TLE pathogenesis most likely involves the aberrant expression of microRNAs (miRNAs). miRNAs play an essential role in organism homeostasis and are widely studied in TLE as potential therapeutics and biomarkers. However, many discrepancies in discovered miRNAs occur among TLE studies due to model-specific miRNA expression, different onset ages of epilepsy among patients, or technology-related bias. We employed a massive parallel sequencing approach to analyze brain tissues from 16 adult mesial TLE (mTLE)/hippocampal sclerosis (HS) patients, 8 controls and 20 rats with TLE-like syndrome, and 20 controls using the same workflow and categorized these subjects based on the age of epilepsy onset. All categories were compared to discover overlapping miRNAs with an aberrant expression, which could be involved in TLE. Our cross-comparative analyses showed distinct miRNA profiles across the age of epilepsy onset and found that the miRNA profile in rats with adult-onset TLE shows the closest resemblance to the profile in mTLE/HS patients. Additionally, this analysis revealed overlapping miRNAs between patients and the rat model, which should participate in epileptogenesis and ictogenesis. Among the overlapping miRNAs stand out miR-142-5p and miR-142-3p, which regulate immunomodulatory agents with pro-convulsive effects and suppress neuronal growth. Our cross-comparison study enhanced the insight into the effect of the age of epilepsy onset on miRNA expression and deepened the knowledge of epileptogenesis. We employed the same methodological workflow in both patients and the rat model, thus improving the reliability and accuracy of our results.

• Klíčová slova
• animal model, cross-comparison study, human, mesial temporal lobe epilepsy, miRNA, sequencing,
• Publikační typ
• časopisecké články MeSH