Focal cortical dysplasia(FCD)is one of the most common causes of drug-resistant epilepsy.Dysmorphic neurons are the major histopathological feature of typeⅡFCD,but their role in seizure genesis in FCD is unclear.Here...Focal cortical dysplasia(FCD)is one of the most common causes of drug-resistant epilepsy.Dysmorphic neurons are the major histopathological feature of typeⅡFCD,but their role in seizure genesis in FCD is unclear.Here we performed whole-cell patch-clamp recording and morphological reconstruction of cortical principal neurons in postsurgical brain tissue from drug-resistant epilepsy patients.Quantitative analyses revealed distinct morphological and electrophysiological characteristics of the upper layer dysmorphic neurons in typeⅡFCD,including an enlarged soma,aberrant dendritic arbors,increased current injection for rheobase action potential firing,and reduced action potential firing frequency.Intriguingly,the upper layer dysmorphic neurons received decreased glutamatergic and increased GABAergic synaptic inputs that were coupled with upregulation of the Na^(+)-K^(+)-Cl^(−)cotransporter.In addition,we found a depolarizing shift of the GABA reversal potential in the CamKⅡ-cre::PTENflox/flox mouse model of drug-resistant epilepsy,suggesting that enhanced GABAergic inputs might depolarize dysmorphic neurons.Thus,imbalance of synaptic excitation and inhibition of dysmorphic neurons may contribute to seizure genesis in typeⅡFCD.展开更多
Brain-specific loss of a microtubule-binding protein collapsin response mediator protein-2(CRMP2)in the mouse recapitulates many schizophrenia-like behaviors of human patients,possibly resulting from associated develo...Brain-specific loss of a microtubule-binding protein collapsin response mediator protein-2(CRMP2)in the mouse recapitulates many schizophrenia-like behaviors of human patients,possibly resulting from associated developmental deficits in neuronal differentiation,path-finding,and synapse formation.However,it is still unclear how the Crmp2 loss affects neuronal circuit function and plasticity.By conducting in vivo and ex vivo electrophysiological recording in the mouse primary visual cortex(V1),we reveal that CRMP2 exerts a key regulation on the timing of postnatal critical period(CP)for experience-dependent circuit plasticity of sensory cortex.In the developing V1,the Crmp2 deficiency induces not only a delayed maturation of visual tuning functions but also a precocious CP for visual input-induced ocular dominance plasticity and its induction activity–coincident binocular inputs right after eye-opening.Mechanistically,the Crmp2 deficiency accelerates the maturation process of cortical inhibitory transmission and subsequently promotes an early emergence of balanced excitatory-inhibitory cortical circuits during the postnatal development.Moreover,the precocious CP plasticity results in deteriorated binocular depth perception in adulthood.Thus,these findings suggest that the Crmp2 deficiency dysregulates the timing of CP for experience-dependent refinement of circuit connections and further leads to impaired sensory perception in later life.展开更多
基金supported by grants from the Ministry of Science and Technology(2019YFA0110103)the National Natural Science Foundation of China(81870898,82071287,and 81870916)+1 种基金the Fundamental Research Funds for the Central Universities(2019FZA7009 and 2021FZZX001-37)the Zhejiang Provincial Natural Science Foundation(LR18H090002).
文摘Focal cortical dysplasia(FCD)is one of the most common causes of drug-resistant epilepsy.Dysmorphic neurons are the major histopathological feature of typeⅡFCD,but their role in seizure genesis in FCD is unclear.Here we performed whole-cell patch-clamp recording and morphological reconstruction of cortical principal neurons in postsurgical brain tissue from drug-resistant epilepsy patients.Quantitative analyses revealed distinct morphological and electrophysiological characteristics of the upper layer dysmorphic neurons in typeⅡFCD,including an enlarged soma,aberrant dendritic arbors,increased current injection for rheobase action potential firing,and reduced action potential firing frequency.Intriguingly,the upper layer dysmorphic neurons received decreased glutamatergic and increased GABAergic synaptic inputs that were coupled with upregulation of the Na^(+)-K^(+)-Cl^(−)cotransporter.In addition,we found a depolarizing shift of the GABA reversal potential in the CamKⅡ-cre::PTENflox/flox mouse model of drug-resistant epilepsy,suggesting that enhanced GABAergic inputs might depolarize dysmorphic neurons.Thus,imbalance of synaptic excitation and inhibition of dysmorphic neurons may contribute to seizure genesis in typeⅡFCD.
基金the National Natural Science Foundation of China(32071025,31921002,and 31730108)the Beijing Municipal Science&Technology Commission(Z181100001518001)+1 种基金the Interdisciplinary Research Fund of Beijing Normal Universitythe Strategic Priority Research Program and Innovation Program of the Chinese Academy of Sciences(XDB32020100)。
文摘Brain-specific loss of a microtubule-binding protein collapsin response mediator protein-2(CRMP2)in the mouse recapitulates many schizophrenia-like behaviors of human patients,possibly resulting from associated developmental deficits in neuronal differentiation,path-finding,and synapse formation.However,it is still unclear how the Crmp2 loss affects neuronal circuit function and plasticity.By conducting in vivo and ex vivo electrophysiological recording in the mouse primary visual cortex(V1),we reveal that CRMP2 exerts a key regulation on the timing of postnatal critical period(CP)for experience-dependent circuit plasticity of sensory cortex.In the developing V1,the Crmp2 deficiency induces not only a delayed maturation of visual tuning functions but also a precocious CP for visual input-induced ocular dominance plasticity and its induction activity–coincident binocular inputs right after eye-opening.Mechanistically,the Crmp2 deficiency accelerates the maturation process of cortical inhibitory transmission and subsequently promotes an early emergence of balanced excitatory-inhibitory cortical circuits during the postnatal development.Moreover,the precocious CP plasticity results in deteriorated binocular depth perception in adulthood.Thus,these findings suggest that the Crmp2 deficiency dysregulates the timing of CP for experience-dependent refinement of circuit connections and further leads to impaired sensory perception in later life.
