Neurodegeneration and Repair Lab, Department of Pathology, Postgraduate Program in Anatomical Pathology, Faculty of Medicine, Universitary Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
D'Or Institute for Research and Teaching, Rio de Janeiro, Brazil.
Epilepsia Open. 2022 Sep;7(3):462-473. doi: 10.1002/epi4.12625. Epub 2022 Jul 21.
Malformations of the polymicrogyria spectrum can be mimicked in rodents through neonatal transcranial focal cortical freeze lesions. The animals presenting the malformations present both altered synaptic events and epileptiform activity in the vicinity of the microgyrus, but the comprehension of their contribution to increased predisposition or severity of seizures require further studies.
In order to investigate these issues, we induced both microgyria and schizencephaly in 57 mice and evaluated: their convulsive susceptibility and severity after pentyleneterazol (PTZ) treatment, the quantification of their symmetric and asymmetric synapses, the morphology of their dendritic arbors, and the content of modulators of synaptogenesis, such as SPARC, gephyrin and GAP-43 within the adjacent visual cortex.
Our results have shown that only schizencephalic animals present increased convulsive severity. Nevertheless, both microgyric and schizencephalic cortices present increased synapse number and dendritic complexity of layer IV and layer V-located neurons. Specifically, the microgyric cortex presented reduced inhibitory synapses, while the schizencephalic cortex presented increased excitatory synapses. This altered synapse number is correlated with decreased content of both the anti-synaptogenic factor SPARC and the inhibitory postsynaptic organizer gephyrin in both malformed groups. Besides, GAP-43 content and dendritic spines number are enhanced exclusively in schizencephalic cortices.
In conclusion, our study supports the hypothesis that the sum of synaptic alterations drives to convulsive aggravation in animals with schizencephaly, but not microgyria after PTZ treatment. These findings reveal that different malformations of cortical development should trigger epilepsy via different mechanisms, requiring further studies for development of specific therapeutic interventions.
通过新生鼠颅顶皮质冷冻损伤，可在啮齿动物中模拟多微小脑回畸形。存在畸形的动物在微脑回附近既有改变的突触事件又有癫痫样活动，但对其增加癫痫易感性或严重程度的贡献的理解需要进一步研究。
为了研究这些问题，我们在 57 只小鼠中诱导了微脑回和脑裂畸形，并评估了：它们在戊四氮（PTZ）处理后的惊厥易感性和严重程度、对称和不对称突触的定量、树突分支形态以及突触发生调节剂（如 SPARC、神经胶质纤维酸性蛋白和 GAP-43）在相邻视皮层中的含量。
我们的结果表明，只有脑裂畸形动物的惊厥严重程度增加。然而，微脑回和脑裂畸形皮质都表现出第四层和第五层神经元的突触数量增加和树突复杂性增加。具体而言，微脑回皮质的抑制性突触减少，而脑裂畸形皮质的兴奋性突触增加。这种改变的突触数量与抗突触形成因子 SPARC 和抑制性突触后组织因子神经胶质纤维酸性蛋白的含量降低相关，这两种因子在两个畸形组中都减少。此外，GAP-43 含量和树突棘数量仅在脑裂畸形皮质中增强。
总之，我们的研究支持这样一种假设，即突触改变的总和导致脑裂畸形动物在 PTZ 处理后癫痫加重，但不会导致微脑回畸形动物的癫痫加重。这些发现表明，不同的皮质发育畸形可能通过不同的机制引发癫痫，需要进一步研究以开发特定的治疗干预措施。
