Mutations in the GABAA receptor ␥2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a ␥2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of ␥2(R43Q) was seen in heterozygous mice in the absence of any change in ␣1 subunit surface expression, ruling out a dominant-negative effect. GABA Amediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.GABAA receptor ͉ genetics ͉ electroencephalogram ͉ trafficking ͉ synapse G ABA A receptors in the adult brain are important for inhibiting the activity of neurons in which they reside. Dysfunction of these receptors caused by familial mutations can give rise to febrile seizures (FS) and a variety of generalized epilepsy phenotypes (1-3). To date, five mutations have been reported in the GABA A ␥2 subunit gene with an array of seizure types seen in patients (1, 4-7). Childhood absence epilepsy (CAE) and FS were the main phenotypes in a large Australian family with an arginine to glutamine mutation at position 43 (R43Q) in the GABA A ␥2 subunit gene (1,8).Understanding how the GABA A ␥2(R43Q) mutation causes epilepsy is difficult. GABA A receptors themselves serve several roles. They regulate moment-to-moment brain function (9), play an important role in brain development (10), and have key roles in neuronal plasticity (11, 12) and response to brain injury (13-15). Epilepsy itself is a complex phenomenon involving the interaction of multiple cell types in networks within and between different brain regions that are likely to be influenced by GABA A receptor dysfunction caused by the R43Q mutation. Furthermore, in vitro analyses of the consequences of this mutation have shown inconsistent findings with a range of deficits in receptor pharmacology, trafficking, kinetics, or assembly (16-23) potentially implicated in disease pathogenesis.Clearly, the complex nature of epileptogenesis demands in vivo investigation. Genetic epilepsies provide a framework on which to investigate the consequences of causative mutations at a range of organizational levels within the brain, creating a chain of understanding from molecules to behavior. Linking this chain is impossible in humans because of the highly invasive methodology required and is severely limited in heterologous expression systems that lack necessary complexity. Mice mod...
Auxetic composite materials can be produced either from conventional components via specially designed configurations or from auxetic components. This paper reviews manufacturing methods for both these scenarios. It then looks at the possibility of property enhancements in both low velocity impact and fibre pull out due to the negative Poisson's ratio. Tests revealed that auxetic carbon fibre composites made from commercially available prepreg show evidence of increased resistance to low velocity impact and static indentation with a smaller area of damage. Also, using auxetic fibres in composite materials is shown to produce a higher resistance to fibre pullout.
Development of appropriate dendritic arbors is crucial for neuronal information transfer. We show, using seizure-related gene 6 (sez-6) null mutant mice, that Sez-6 is required for normal dendritic arborization of cortical neurons. Deep-layer pyramidal neurons in the somatosensory cortex of sez-6 null mice exhibit an excess of short dendrites, and cultured cortical neurons lacking Sez-6 display excessive neurite branching. Overexpression of individual Sez-6 isoforms in knockout neurons reveals opposing actions of membrane-bound and secreted Sez-6 proteins, with membrane-bound Sez-6 exerting an antibranching effect under both basal and depolarizing conditions. Layer V pyramidal neurons in knockout brain slices show reduced excitatory postsynaptic responses and a reduced dendritic spine density, reflected by diminished punctate staining for postsynaptic density 95 (PSD-95). In behavioral tests, the sez-6 null mice display specific exploratory, motor, and cognitive deficits. In conclusion, cell-surface protein complexes involving Sez-6 help to sculpt the dendritic arbor, in turn enhancing synaptic connectivity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.