Behavioral Impairments in Rats with Focal Cortical Dysplasia Following Febrile Seizures

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Disruptions in cerebral cortex development during early ontogenesis often lead to pharmacoresistant epilepsy and mental disorders. One such disruption is focal cortical dysplasia (FCD), which can be modeled in experimental animals by inducing cryogenic injury to the neocortex on the first day after birth. FCD is frequently associated with the development of epilepsy and behavioral impairments, such as deficits in learning, memory, and social interaction. These effects may be more pronounced when the brain is exposed to additional challenges, such as the combination of FCD with neonatal febrile seizures (FS). However, the specific characteristics of behavioral impairments in this combined pathology remain poorly understood. This study aimed to investigate behavioral impairments in adult male Wistar rats with FCD who had experienced FS. FCD was induced in rat pups on the first day of life (P0) by localized freezing of the somatosensory cortex. On the 10th day of life (P10), FS were triggered in the rat pups through hyperthermia (exposure to warm air) for 30 minutes. Only animals with FS lasting at least 15 minutes were included in the study. The control group consisted of sham-operated rat pups that were separated from their mother for 30 minutes at P10 without exposure to heat. At 2–2.5 months of age, the animals' behavior was evaluated using the following tests: Open Field, Elevated Plus Maze, Social Interaction Test, and Spontaneous Alternation Test in the Y-Maze. The results revealed that the combination of FCD and FS in early life led to increased social activity and alterations in exploratory behavior and anxiety levels in adult rats. These findings suggest that the combined pathology selectively affects behavioral functions, potentially due to the reorganization of neural networks in the brain. The study expands our understanding of the consequences of FCD and FS on brain function development and highlights the need for further research into the mechanisms underlying these changes. This work may contribute to the development of new therapeutic strategies for patients with similar conditions.

Full Text

Restricted Access

About the authors

O. E. Zubareva

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: zubarevaOE@mail.ru
Russian Federation, Saint Petersburg

D. S. Sinyak

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zubarevaOE@mail.ru
Russian Federation, Saint Petersburg

M. R. Subhankulov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zubarevaOE@mail.ru
Russian Federation, Saint Petersburg

T. Yu. Postnikova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zubarevaOE@mail.ru
Russian Federation, Saint Petersburg

A. V. Zaytsev

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zubarevaOE@mail.ru
Russian Federation, Saint Petersburg

References

  1. Ho CSH, Dubeau F, Séguin R, Ducharme S (2019) Prevalence of neuropsychiatric symptoms associated with malformations of cortical development. Epilepsy and Behavior 92: 306–310. https://doi.org/10.1016/j.yebeh.2019.01.011
  2. Ma Q, Chen G, Li Y, Guo Z, Zhang X (2024) The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development. Genes Dis 11: 101021. https://doi.org/10.1016/j.gendis.2023.04.041
  3. Desikan RS, Barkovich AJ (2016) Malformations of cortical development. Ann Neurol 80: 797–810. https://doi.org/10.1002/ana.24793
  4. Crino PB (2015) Focal cortical dysplasia. Semin Neurol 35: 201–208. https://doi.org/10.1055/s-0035-1552617
  5. Zhao Y, Lin J, Qi X, Cao D, Zhu F, Chen L, Tan Z, Mo T, Zeng H (2024) To explore the potential mechanisms of cognitive impairment in children with MRI-negative pharmacoresistant epilepsy due to focal cortical dysplasia: A pilot study from gray matter structure view. Heliyon 10: e26609. https://doi.org/10.1016/j.heliyon.2024.e26609
  6. Choi SA, Kim KJ (2019) The Surgical and Cognitive Outcomes of Focal Cortical Dysplasia. J Korean Neurosurg Soc 62: 321–327. https://doi.org/10.3340/jkns.2019.0005
  7. Allone C, Bonanno L, Lo Buono V, Corallo F, Palmeri R, Micchia K, Pollicino P, Bramanti A, Marino S (2020) Neuropsychological assessment and clinical evaluation in temporal lobe epilepsy with associated cortical dysplasia. J Clin Neurosci 72: 146–150. https://doi.org/10.1016/j.jocn.2019.12.041
  8. Kimura N, Takahashi Y, Shigematsu H, Imai K, Ikeda H, Ootani H, Takayama R, Mogami Y, Kimura N, Baba K, Kondou S, Inoue Y (2019) Risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia. Brain Dev 41: 77–84. https://doi.org/10.1016/j.braindev.2018.07.014
  9. Qiao L, Yu T, Ni D, Wang X, Xu C, Liu C, Zhang G, Li Y (2017) Correlation between extreme fear and focal cortical dysplasia in anterior cingulate gyrus: Evidence from a surgical case of refractory epilepsy. Clin Neurol Neurosurg 163: 121–123. https://doi.org/10.1016/j.clineuro.2017.10.025
  10. Fujimoto A, Enoki H, Niimi K, Nozaki T, Baba S, Shibamoto I, Otsuki Y, Oanishi T (2021) Epilepsy in patients with focal cortical dysplasia may be associated with autism spectrum disorder. Epilepsy and Behavior 120: 107990. https://doi.org/10.1016/j.yebeh.2021.107990
  11. Luhmann HJ (2023) Malformations-related neocortical circuits in focal seizures. Neurobiol Dis 178: 106018. https://doi.org/10.1016/j.nbd.2023.106018
  12. Dvorák K, Feit J (1977) Migration of neuroblasts through partial necrosis of the cerebral cortex in newborn rats-contribution to the problems of morphological development and developmental period of cerebral microgyria. Histological and autoradiographical study. Acta Neuropathol 38: 203–212. https://doi.org/10.1007/BF00688066
  13. Sanon NT, Desgent S, Carmant L (2012) Atypical Febrile Seizures, Mesial Temporal Lobe Epilepsy, and Dual Pathology. Epilepsy Res Treat 2012: 1–9. https://doi.org/10.1155/2012/342928
  14. Bernard C (2016) The Diathesis–Epilepsy Model: How Past Events Impact the Development of Epilepsy and Comorbidities. Cold Spring Harb Perspect Med 6: a022418. https://doi.org/10.1101/cshperspect.a022418
  15. Jacobs KM, Gutnick MJ, Prince DA (1996) Hyperexcitability in a Model of Cortical Maldevelopment. Cerebr Cortex 6: 514–523. https://doi.org/10.1093/cercor/6.3.514
  16. Luhmann HJ, Raabe K (1996) Characterization of neuronal migration disorders in neocortical structures: I. Expression of epileptiform activity in an animal model. Epilepsy Res 26: 67–74. https://doi.org/10.1016/S0920-1211(96)00041-1
  17. Luhmann HJ, Raabe K, Qü M, Zilles K (1998) Characterization of neuronal migration disorders in neocortical structures: Еxtracellular in vitro recordings. Eur J Neurosci 10: 3085–3094. https://doi.org/10.1046/j.1460-9568.1998.00311.x
  18. Malkin SL, Amakhin DV, Soboleva EB, Postnikova TY, Zaitsev AV (2025) Synaptic Dysregulation Drives Hyperexcitability in Pyramidal Neurons Surrounding Freeze-Induced Neocortical Malformations in Rats. Int J Mol Sci 2025: 1423. https://doi.org/10.3390/ijms26041423
  19. Colciaghi F, Finardi A, Frasca A, Balosso S, Nobili P, Carriero G, Locatelli D, Vezzani A, Battaglia G (2011) Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia. Brain 134: 2828–2843. https://doi.org/10.1093/brain/awr045
  20. Ouardouz M, Lema P, Awad PN, Di Cristo G, Carmant L (2010) N-methyl-D-aspartate, hyperpolarization-activated cation current (Ih) and gamma-aminobutyric acid conductances govern the risk of epileptogenesis following febrile seizures in rat hippocampus. Eur J Neurosci 31: 1252–1260. https://doi.org/10.1111/j.1460-9568.2010.07159.x
  21. Scantlebury MH, Gibbs SA, Foadjo B, Lema P, Psarropoulou C, Carmant L (2005) Febrile seizures in the predisposed brain: A new model of temporal lobe epilepsy. Ann Neurol 58: 41–49. https://doi.org/10.1002/ana.20512
  22. Postnikova TY, Griflyuk AV, Amakhin DV, Kovalenko AA, Soboleva EB, Zubareva OE, Zaitsev AV (2021) Early Life Febrile Seizures Impair Hippocampal Synaptic Plasticity in Young Rats. Int J Mol Sci 22: 8218. https://doi.org/10.3390/ijms22158218
  23. Savage S, Kehr J, Olson L, Mattsson A (2011) Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation. Neuroscience 195: 60–69. https://doi.org/10.1016/j.neuroscience.2011.08.027
  24. Singh M, Singh KP, Shukla S, Dikshit M (2015) Assessment of in-utero venlafaxine induced, ROS-mediated, apoptotic neurodegeneration in fetal neocortex and neurobehavioral sequelae in rat offspring. Int J Development Neurosci 40: 60–69. https://doi.org/10.1016/j.ijdevneu.2014.10.007
  25. Prinzi C, Kostenko A, de Leo G, Gulino R, Leanza G, Caccamo A (2023) Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins. Biology (Basel) 12: 1264. https://doi.org/10.3390/biology12091264
  26. Sapiurka M, Squire LR, Clark RE (2016) Distinct roles of hippocampus and medial prefrontal cortex in spatial and nonspatial memory. Hippocampus 26: 1515–1524. https://doi.org/10.1002/hipo.22652
  27. Rosen GD, Waters NS, Galaburda AM, Denenberg VH (1995) Behavioral consequences of neonatal injury of the neocortex. Brain Res 681: 177–189. https://doi.org/10.1016/0006-8993(95)00312-E
  28. Clark MG, Rosen GD, Tallal P, Fitch RH (2000) Impaired processing of complex auditory stimuli in rats with induced cerebrocortical microgyria: An animal model of developmental language disabilities. J Cogn Neurosci 12: 828–839. https://doi.org/10.1162/089892900562435
  29. Bast T, Ramantani G, Seitz A, Rating D (2006) Focal cortical dysplasia: Prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol Scand 113: 72–81. https://doi.org/10.1111/j.1600-0404.2005.00555.x
  30. Mattia D, Olivier A, Avoli M (1995) Seizure‐like discharges recorded in human dysplastic neocortex maintained in vitro. Neurology 45: 1391–1395. https://doi.org/10.1212/WNL.45.7.1391
  31. Yu YH, Lee K, Sin DS, Park K-H, Park D-K, Kim D-S (2017) Altered functional efficacy of hippocampal interneuron during epileptogenesis following febrile seizures. Brain Res Bull 131: 25–38. https://doi.org/10.1016/j.brainresbull.2017.02.009
  32. Sloviter RS (1999) Status epilepticus-induced neuronal injury and network reorganization. Epilepsia 40: s34–s39. https://doi.org/10.1111/j.1528-1157.1999.tb00876.x
  33. Hoogland G, Raijmakers M, Clynen E, Brône B, Rigo J-M, Swijsen A (2022) Experimental early-life febrile seizures cause a sustained increase in excitatory neurotransmission in newborn dentate granule cells. Brain Behav 12: e2505. https://doi.org/10.1002/brb3.2505
  34. Yu YH, Kim S-W, Im H, Lee YR, Kim GW, Ryu S, Park D-K, Kim D-S (2023) Febrile Seizure Causes Deficit in Social Novelty, Gliosis, and Proinflammatory Cytokine Response in the Hippocampal CA2 Region in Rats. Cells 12: 2446. https://doi.org/10.3390/cells12202446
  35. Kloc ML, Marchand DH, Holmes GL, Pressman RD, Barry JM (2022) Cognitive impairment following experimental febrile seizures is determined by sex and seizure duration. Epilepsy & Behavior 126: 108430. https://doi.org/10.1016/j.yebeh.2021.108430
  36. Sheppard E, Lalancette E, Thébault-Dagher F, Lafontaine M-P, Knoth IS, Gravel J, Lippé S (2021) Cognitive and behavioural development in children presenting with complex febrile seizures: Аt onset and school age. Epilept Disord 23: 325–336. https://doi.org/10.1684/epd.2021.1260
  37. Martinos MM, Yoong M, Patil S, Chin RFM, Neville BG, Scott RC, de Haan M (2012) Recognition memory is impaired in children after prolonged febrile seizures. Brain 135: 3153–3164. https://doi.org/10.1093/brain/aws213
  38. Griflyuk AV, Postnikova TY, Zaitsev AV (2024) Animal Models of Febrile Seizures: Limitations and Recent Advances in the Field. Cells 13: 1895. https://doi.org/10.3390/cells13221895
  39. Remonde CG, Gonzales EL, Adil KJ, Jeon SJ, Shin CY (2023) Augmented impulsive behavior in febrile seizure-induced mice. Toxicol Res 39: 37–51. https://doi.org/10.1007/s43188-022-00145-1
  40. Yu YH, Kim S-W, Im H, Song Y, Kim SJ, Lee YR, Kim GW, Hwang C, Park D-K, Kim D-S (2022) Febrile Seizures Cause Depression and Anxiogenic Behaviors in Rats. Cells 11: 3228. https://doi.org/10.3390/cells11203228
  41. Gibbs S, Chattopadhyaya B, Desgent S, Awad PN, Clerk-Lamalice O, Levesque M, Vianna RM, Rébillard RM, Delsemme AA, Hébert D, Tremblay L, Lepage M, Descarries L, Di Cristo G, Carmant L (2011) Long-term consequences of a prolonged febrile seizure in a dual pathology model. Neurobiol Dis 43: 312–321. https://doi.org/10.1016/j.nbd.2011.02.013
  42. Desgent S, Duss S, Sanon NT, Lema P, Lévesque M, Hébert D, Rébillard R-M, Bibeau K, Brochu M, Carmant L (2012) Early-Life Stress Is Associated with Gender-Based Vulnerability to Epileptogenesis in Rat Pups. PLoS One 7: e42622. https://doi.org/10.1371/journal.pone.0042622
  43. Sotoyama H, Inaba H, Iwakura Y, Namba H, Takei N, Sasaoka T, Nawa H (2022) The dual role of dopamine in the modulation of information processing in the prefrontal cortex underlying social behavior. FASEB J 36: e22160. https://doi.org/10.1096/fj.202101637R
  44. Adinolfi A, Carbone C, Leo D, Gainetdinov RR, Laviola G, Adriani W (2018) Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns. Genes Brain Behav 17: e12463. https://doi.org/10.1111/gbb.12463
  45. Liu L, Zhang L, Wang T, Chen L (2019) Dopamine D1 receptor in the medial prefrontal cortex mediates anxiety-like behaviors induced by blocking glutamatergic activity of the ventral hippocampus in rats. Brain Res 1704: 59–67. https://doi.org/10.1016/j.brainres.2018.09.024
  46. Trottier S, Evrard B, Biraben A, Chauvel P (1994) Altered patterns of catecholaminergic fibers in focal cortical dysplasia in two patients with partial seizures. Epilepsy Res 19: 161–179. https://doi.org/10.1016/0920-1211(94)90026-4

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Freezing-induced cortical malformation. (a) - Representative example of a rat brain (P21) that sustained freezing-induced damage at age P0, resulting in a longitudinal microhyria in the left sensorimotor cortex (dashed line). (b) - Schematic representation of freezing-induced microhyria. (c) - Representative example of Nissl stained coronal slices through a dysplastic lesion in the rat cerebral cortex. The image clearly shows the formed four-layer microgyria. The location of the freezing centre is indicated by the black arrow.

Download (503KB)
Indexing metadata
3. Fig. 2. Motor activity of control (Ctrl) and experimental (FCD + FC) rats. (a) - Tracks in the Open Field test. (b) - Distance travelled in the Open Field test. (c) - Speed of locomotion in the Open Field test. (d) - Locomotion time in the Open Field. (e) - Number of arms examined in the ‘Y-maze’ test.

Download (304KB)
Indexing metadata
4. Fig. 3. Exploratory activity of control (Ctrl) and experimental (FCD + FC) rats. (a, b) - Number and time of examinations of burrows in the ‘Open field’ test. (c, d) - Mean time and number of examinations of the same objects in the ‘Exploration and recognition of new objects’ test. * - p < 0.05; Student's t-test.

Download (138KB)
Indexing metadata
5. Fig. 4. Anxiety level scores of control (Ctrl) and experimental (FCD + FC) rats. (a-c) - Absolute and relative time spent in open and closed arms in the Elevated Cross Maze test. (d, e) - Number of episodes and grooming time in the Open Field test. * - p < 0.05; Student's t-test.

Download (165KB)
Indexing metadata
6. Fig. 5. Social behaviour of control (Ctrl) and experimental (FCD + FC) rats in the ‘Social Test’. (a) - Total communication time. (b) - Sniffing the genital area. (c) - Body sniffing and grooming. (d) - Duration of aggressive behaviour. * - p < 0.05; *** - p < 0.001; Student's t-test.

Download (106KB)
Indexing metadata
7. Fig. 6. Memory performance of control (Ctrl) and experimental (FCD + FC) rats in the ‘Y-maze’ test (a, b) and in the ‘Recognition of new objects’ test (c, d). Data are presented as mean and standard error of the mean (a, c, d) or as medians and interquartile ranges (b). & - Differences in the time course of familiar and novel objects in the control group; # - differences in the time course of familiar and novel objects in the experimental group; p < 0.05; paired t-test with Bonferroni correction.

Download (170KB)
Indexing metadata

Copyright (c) 2025 Russian Academy of Sciences