Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders

2021 ◽  
Author(s):  
Ana Uzquiano
Keyword(s):  
Neuronal Migration ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Neuronal Migration Disorders ◽  
Migration Disorders

Characterization of Neuronal Migration Disorders in Neocortical Structures. II. Intracellular In Vitro Recordings

1998 ◽  
Vol 80 (1) ◽  
pp. 92-102 ◽  
Author(s):  
Heiko J. Luhmann ◽  
Nikolai Karpuk ◽  
Meishu Qü ◽  
Karl Zilles
Keyword(s):  
Nmda Receptors ◽  
Neuronal Migration ◽  
Epileptiform Activity ◽  
Membrane Potentials ◽  
Membrane Properties ◽  
Neuronal Migration Disorders ◽  
Intrinsic Membrane Properties ◽  
Migration Disorders

Luhmann, Heiko J., Nikolai Karpuk, Meishu Qü, and Karl Zilles. Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings. J. Neurophysiol. 80: 92–102, 1998. Neuronal migration disorders (NMD) are involved in a variety of different developmental disturbances and in therapy-resistant epilepsy. The cellular mechanisms underlying the pronounced hyperexcitability in dysplastic cortex are not well understood and demand further clinical and experimental analyses. We used a focal freeze-lesion model in cerebral cortex of newborn rats to study the functional consequences of NMD. Intracellular recordings from supragranular regular spiking cells in cortical slices from adult sham-operated rats revealed normal passive and active intrinsic membrane properties and normal stimulus-evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively). Regular spiking neurons recorded in rat dysplastic cortex showed on average a significantly smaller action potential amplitude, a slower spike rise, and a less steep primary frequency-current relationship. Stimulus-elicited EPSPs in NMD-affected cortex consisted of multiphasic burst discharges, which coincided with extracellular field potentials and lasted 150–800 ms. These epileptiform responses could be recorded at membrane potentials between −50 and −110 mV and were blocked by dl−2-amino-5-phosphonovaleric acid (APV), indicating the involvement of N-methyl-d-aspartate (NMDA) receptors. Isolated NMDA-mediated and APV-sensitive EPSPs could be recorded at membrane potentials negative to −70 mV, suggesting that NMDA receptors are activated at relatively negative membrane potentials. In comparison with the controls, polysynaptic IPSPs mediated by the γ-aminobutyric acid (GABA) type A and B receptor were either absent or reduced in peak conductance in microgyric cortex by 27% ( P < 0.05) and 17%, respectively. However, monosynaptic IPSPs recorded in the presence of ionotropic glutamate receptor antagonists revealed a similar efficacy in NMD and control cortex, indicating that GABAergic neurons in microgyric cortex get a weaker excitatory input. Our data indicate that the expression of epileptiform activity in NMD-affected cortex rather results from an imbalance between excitatory and inhibitory synaptic transmission than from alterations in the intrinsic membrane properties. This imbalance is caused by an increase in NMDA-receptor–mediated excitation in pyramidal neurons and a concurrent decrease of glutamatergic input onto inhibitory interneurons.

scholarly journals Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders

2021 ◽  
Author(s):  
Martina Riva ◽  
Sofia Ferreira ◽  
Vera P. Medvedeva ◽  
Frédéric Causeret ◽  
Olivia J. Henry ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
De Novo ◽  
Functional Characterization ◽  
Valuable Insight ◽  
Embryonic Mouse ◽  
Cortical Malformations ◽  
Neuronal Migration Disorders ◽  
Migration Disorders

RELN is a large secreted glycoprotein that acts at multiple steps of cerebral cortex development, including neuronal migration. Only recessive mutations of the Reelin gene (RELN) have been associated with human cortical malformations and none has been functionally characterized. We identified novel missense RELN mutations in both compound and de novo heterozygous patients exhibiting an array of neuronal migration disorders (NMDs) as diverse as pachygyria, polymicrogyria and heterotopia. Most mutations caused defective RELN secretion in vitro and, when ectopically expressed in the embryonic mouse cortex, affected neuronal aggregation and/or migration in vivo. We determined the de novo heterozygous mutations acted as dominant negative and demonstrated that RELN mutations mediate not only recessive, but also dominant NMDs. This work assesses for the first time the pathogenicity of RELN mutations showing a strong genotype-phenotype correlation. In particular, the behavior of the mutant proteins in vitro and in vivo predicts the severity of cortical malformations and provides valuable insight into the pathogenesis of these disorders.

Recent Development in Neuronal Migration Disorders: Clinical, Neuroradiologic and Genetics Aspects

2008 ◽  
Vol 4 (4) ◽  
pp. 216-226
Author(s):  
Paola Iannetti ◽  
Alberto Spalice ◽  
Laura Papetti ◽  
Pasquale Parisi
Keyword(s):  
Neuronal Migration ◽  
Neuronal Migration Disorders ◽  
Migration Disorders

NEURONAL MIGRATION DISORDERS (NMD)

1998 ◽  
Vol 57 (5) ◽  
pp. 482 ◽  
Author(s):  
M. C. Lee ◽  
T. S. Lee ◽  
K. H. Yang ◽  
H. I. Kim
Keyword(s):  
Neuronal Migration ◽  
Neuronal Migration Disorders ◽  
Migration Disorders
Sign in / Sign up

Export Citation Format

Share Document