Abstract
Dysfunction of the LIS1 gene causes lissencephaly, a drastic neurological disorder characterized by a deep disruption of the cortical structure. We aim to uncover alterations of the cortical neuronal networks related with the propagation of epileptiform activity in the Lis1/sLis1 mouse, a model lacking the LisH domain in heterozygosis. We did extracellular field-potential and intracellular recordings in brain slices of the anterior cingulate cortex (ACC) or the retrosplenial cortex (RSC) to study epileptiform activity evoked in the presence of bicuculline (10 µM), a blocker of GABAA receptors. The sensitivity to bicuculline of the generation of epileptiform discharges was similar in wild type (WT) and Lis1/sLis1 cortex (EC50 1.99 and 2.24 µM, respectively). In the Lis1/sLis1 cortex, we observed a decreased frequency of the oscillatory post-discharges of the epileptiform events; also, the propagation of epileptiform events along layer 2/3 was slower in the Lis1/sLis1 cortex (WT 47.69 ± 2.16 mm/s, n = 25; Lis1/sLis1 37.34 ± 2.43 mm/s, n = 15; p = 0.004). The intrinsic electrophysiological properties of layer 2/3 pyramidal neurons were similar in WT and Lis1/sLis1 cortex, but the frequency of the spontaneous EPSCs was lower and their peak amplitude higher in Lis1/sLis1 pyramidal neurons. Finally, the propagation of epileptiform activity was differently affected by AMPA receptor blockers: CNQX had a larger effect in both ACC and RSC while GYKI53655 had a larger effect only in the ACC in the WT and Lis1/sLis1 cortex. All these changes indicate that the dysfunction of the LIS1 gene causes abnormalities in the properties of epileptiform discharges and in their propagation along the layer 2/3 in the anterior cingulate cortex and in the restrosplenial cortex.
Highlights
LIS1 is a 46 kDa protein involved in synapse formation, synapse modulation, and neuronal migration, which plays a crucial role during brain development and in adult stage
Following our previous study on epileptiform activity propagation (Rovira and Geijo-Barrientos 2016), we recorded from two different cingulate cortical regions, the anterior cingulate cortex (ACC) and the retrosplenial cortex (RSC; Fig. 1A); these two areas were subdivided further in primary and secondary ACC and dorsal agranular and granular RSC
We performed a set of experiments in the cingulate cortex of Lis1/sLis1 mice, a model lacking the LisH domain in heterozygosis, to understand the impact of this genetic context in the properties of the neocortical networks implicated in the generation of epileptiform activity
Summary
LIS1 is a 46 kDa protein involved in synapse formation, synapse modulation, and neuronal migration, which plays a crucial role during brain development and in adult stage. LisH domain is located in the N-terminus portion and mediates the interaction with other LIS1 peptides to produce a LIS1 homodimer, the functional form of the protein. Dynein is a molecular motor which regulates the dynamics and stability of microtubules during cell growth and movement, and with the transport of cargos along them. These mechanisms are the ones supposed to be altered in classic individuals with lissencephaly since they are directly involved in neuronal migration, axon growth and synapse formation and other partners from the same cascade, such as DXC, produce other forms of lissencephaly with similar pathophysiology (Wynshaw-Boris and Gambello 2001).
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