LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

Abstract

Type I lissencephaly, a neuronal migration disorder characterized by cognitive disability and refractory epilepsy, is often caused by heterozygous mutations in the LIS1 gene. Histopathologies of malformation-associated epilepsies have been well described, but it remains unclear whether hyperexcitability is attributable to disruptions in neuronal organization or abnormal circuit function. Here, we examined the effect of LIS1 deficiency on excitatory synaptic function in the dentate gyrus of hippocampus, a region believed to serve critical roles in seizure generation and learning and memory. Mice with heterozygous deletion of LIS1 exhibited robust granule cell layer dispersion, and adult-born granule cells labeled with enhanced green fluorescent protein were abnormally positioned in the molecular layer, hilus, and granule cell layer. In whole-cell patch-clamp recordings, reduced LIS1 function was associated with greater excitatory synaptic input to mature granule cells that was consistent with enhanced release probability at glutamatergic synapses. Adult-born granule cells that were ectopically positioned in the molecular layer displayed a more rapid functional maturation and integration into the synaptic network compared with newborn granule cells located in the hilus or granule cell layer or in wild-type controls. In a conditional knock-out mouse, induced LIS1 deficiency in adulthood also enhanced the excitatory input to granule cells in the absence of neuronal disorganization. These findings indicate that disruption of LIS1 has direct effects on excitatory synaptic transmission independent of laminar disorganization, and the ectopic position of adult-born granule cells within a malformed dentate gyrus critically influences their functional maturation and integration.

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

“…The architectural alterations of the human cerebral cortex and hippocampus can be somewhat recapitulated in genetically engineered mice. For example, the overexpression of pafah1b1 disturbed neuronal migration and layer formation in the developing cerebral cortex [121], whereas lis1 deficiency in homozygous mice resulted in early embryonic death and in heterozygous mice led to a derangement of the normal hippocampal organization with ectopy of the granule cells [122]. Of note, Lis1, the protein encoded by Pafah1b, is part of the Pafah1b complex and binds, downstream of the Vldlr receptor, to Dab1 that becomes phosphorylated in response to Reln [123].…”

Tubulin mutations in brain development disorders: Why haploinsufficiency does not explain TUBA1A tubulinopathies

“…LIS1 encodes a protein that binds to the dynein motor protein and regulates its function (Smith et al, 2000). Mice with deletions of one copy of Lis1 have cortical and hippocampal layering defects, abnormal excitatory synaptic connections in the dentate gyrus of the hippocampus, deficits in learning and memory, and seizures (Fleck et al, 2000;Greenwood et al, 2009;Hirotsune et al, 1998;Hunt, Dinday, Hindle-Katel, & Baraban, 2012;Paylor et al, 1999;Wang & Baraban, 2007). Human patient phenotypes and mouse models of Lis1 deficiency argue that one copy of Lis1 is not sufficient for brain development.…”

PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus

“…Pafah1b1 is an essential regulator of dynein-mediated motility, as well as mitosis, nuclear positioning, and microtubule organization 27 . Mice with heterozygous deletion of Pafah1b1 exhibit many phenotypes of human lissencephaly, including defects in neuronal migration, disorganization of cortical and hippocampal lamination, deficits in spatial learning and epilepsy 28 – 32 . In acute slice cultures generated from Pafah1b1 +/− mice, putative interneurons migrate ~25% more slowly away from the embryonic ganglionic eminence 33 , 34 , and excitatory synapses on dendrites of dissociated hippocampal interneurons are disorganized 35 .…”