The Ntsr1-Cre GN220 mouse expresses Cre-recombinase in corticothalamic (CT) neurons in neocortical layer 6. It is not known if the other major types of pyramidal neurons in this layer also express this enzyme. By electrophysiological recordings in slices and histological analysis of the uptake of retrogradely transported beads we show that Cre-positive neurons are CT and not corticocortical or corticoclaustral types. Furthermore, we show that Ntsr1-Cre-positive cells are immuno-positive for the nuclear transcription factor Forkhead box protein P2 (FoxP2). We conclude that Cre-expression is limited to a specific type of pyramidal neuron: CT. However, it appears as not all CT neurons are Cre-expressing; there are indications that the penetrance of the gene is about 90%. We demonstrate the utility of assigning a specific identity to individual neurons by determining that the CT neurons are potently modulated by acetylcholine acting on both nicotinic and muscarinic acetylcholine receptors. These results corroborate the suggested function of these neurons in regulating the gain of thalamocortical transfer of sensory information depending on attentional demand and state of arousal.

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The most common excitatory neurotransmitter in the central nervous system, glutamate, is loaded into synaptic vesicles by vesicular glutamate transporters (VGluTs). The primary isoforms, VGluT1 and 2, are expressed in complementary patterns throughout the brain and correlate with short-term synaptic plasticity. VGluT1 deficiency is observed in certain neurological disorders, and hemizygous (VGluT1+/−) mice display increased anxiety and depression, altered sensorimotor gating, and impairments in learning and memory. The synaptic mechanisms underlying these behavioral deficits are unknown. Here, we show that VGluT1+/− mice had decreased visual processing speeds during a sustained visual-spatial attention task. Furthermore, in vitro recordings of corticothalamic (CT) synapses revealed dramatic reductions in short-term facilitation, increased initial release probability, and earlier synaptic depression in VGluT1+/− mice. Our electron microscopy results show that VGluT1 concentration is reduced at CT synapses of hemizygous mice, but other features (such as vesicle number and active zone size) are unchanged. We conclude that VGluT1-haploinsuficiency decreases the dynamic range of gain modulation provided by CT feedback to the thalamus, and this deficiency contributes to the observed attentional processing deficit. We further hypothesize that VGluT1 concentration regulates release probability by applying a “brake” to an unidentified presynaptic protein that typically acts as a positive regulator of release.

Purpose Mutations in apolipoprotein A‐I (apoA‐I) may affect plasma high‐density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA‐I variants. This study investigates whether the apoA‐I mutations, apoA‐IL202P and apoA‐IK131del, are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition. Experimental design Plasma HDL of heterozygotes for either apoA‐IL202P or apoA‐IK131del and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS. Results ApoA‐I peptides containing apoA‐IL202P or apoA‐IK131del were identified in HDL from heterozygotes. The apoA‐IL202P mutant peptide was less abundant than wild‐type peptide while the apoA‐IK131del mutant peptide was more abundant than wild‐type peptide in the heterozygotes. Two‐dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA‐IL202P carriers contained less apoE and more zinc‐α‐2‐glycoprotein while HDL from the apoA‐IK131del heterozygotes contained more alpha‐1‐antitrypsin and transthyretin. Conclusions and clinical relevance Both apoA‐IL202P and apoA‐IK131del were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild‐type apoA‐I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

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