95 research outputs found
Disruption of Kcc2-dependent inhibition of olfactory bulb output neurons suggests its importance in odour discrimination
Synaptic inhibition in the olfactory bulb (OB), the first relay station of
olfactory information, is believed to be important for odour discrimination.
We interfered with GABAergic inhibition of mitral and tufted cells (M/T
cells), the principal neurons of the OB, by disrupting their potassium-
chloride cotransporter 2 (Kcc2). Roughly, 70% of mice died around 3 weeks, but
surviving mice appeared normal. In these mice, the resulting increase in the
intracellular Cl− concentration nearly abolished GABA-induced
hyperpolarization of mitral cells (MCs) and unexpectedly increased the number
of perisomatic synapses on MCs. In vivo analysis of odorant-induced OB
electrical activity revealed increased M/T cell firing rate, altered phasing
of action potentials in the breath cycle and disrupted separation of odour-
induced M/T cell activity patterns. Mice also demonstrated a severely impaired
ability to discriminate chemically similar odorants or odorant mixtures. Our
work suggests that precisely tuned GABAergic inhibition onto M/T cells is
crucial for M/T cell spike pattern separation needed to distinguish closely
similar odours
Disrupting MLC1 and GlialCAM and ClC-2interactions in leukodystrophy entails glial chloridechannel dysfunction
Defects in the astrocytic membrane protein MLC1, the adhesion molecule GlialCAM or the chloride channel ClC-2 underlie human leukoencephalopathies. Whereas GlialCAM binds ClC-2 and MLC1, and modifies ClC-2 currents in vitro, no functional connections between MLC1 and ClC-2 are known. Here we investigate this by generating loss-of-function Glialcam and Mlc1 mouse models manifesting myelin vacuolization. We find that ClC-2 is unnecessary for MLC1 and GlialCAM localization in brain, whereas GlialCAM is important for targeting MLC1 and ClC-2 to specialized glial domains in vivo and for modifying ClC-2's biophysical properties specifically in oligodendrocytes (OLs), the cells chiefly affected by vacuolization. Unexpectedly, MLC1 is crucial for proper localization of GlialCAM and ClC-2, and for changing ClC-2 currents. Our data unmask an unforeseen functional relationship between MLC1 and ClC-2 in vivo, which is probably mediated by GlialCAM, and suggest that ClC-2 participates in the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts
Social Class
Discussion of class structure in fifth-century Athens, historical constitution of theater audiences, and the changes in the comic representation of class antagonism from Aristophanes to Menander
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