engleski

The molecular basis of behavioural traits in ganglioside synthesis deficient mice

Gangliosides are membrane glycosphingolipids of all vertebrate cells, playing role in maturation, synaptogenesis, myelination and plasticity. The major four structures (GM1, GD1a, GD1b and GT1b) dominate mammalian brains. Deficits in ganglioside biosynthesis are rare, accompanied by variable degree of spasticity and intellectual disability. Contrary to still biochemically unexplored human mutations, mouse B4Galt1 knockout (KO) has no residual enzyme activity while less complex structure (GM3/GD3) compensate for the major four. In this model hyperactivity appears as early phenotype feature while inclination to audiogenic seizures appears later. KO also develop severe demyelination and hind limb spasticity due to lack of GD1a/GT1b and myelin associated glycoprotein (MAG) interaction. Onset of each phenotypic feature varies between animals. KO mice were compared to cuprizone (CU) induced demyelination at 3 and 6 months age using behavioural testing, MR imaging and biochemical markers of axon and myelin stability (SMI312, tau, MBP, MAG, CNP-ase). Ratio of excitatory (pyramidal) to inhibitory (interneurons) in wild type (WT) and KO mice was detected by general (NeuN and GABA) and specific (parvalbumin, calbindin, calreticulin and nNOS) neuronal markers. Inflammation was detected by IBA1 and GFAP. Axon and myelin stability was compromised in different extent in KO and CU animals compared to WT. CU treated animals developed less severe hyperactivity and spasticity compared to KO and especially to cuprizone treated KO. Also, number of interneuron was different between experimental groups. Demyelination itself can explain spasticity and hyperactivity, while disturbance in ration of interneurons is additional factor influencing variability in onset of symptoms.

Gangliosides ; B4Galt1 knockout mice ; Cuprizone ; MR imagining ; Demyelination

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