11 research outputs found
Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum
The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity
Disruption of an AP-2 alpha binding site in an IRF6 enhancer is associated with cleft lip
Previously we have shown that nonsyndromic cleft lip with or
without cleft palate (NSCL/P)1 is strongly associated with
SNPs in IRF6 (interferon regulatory factor 6)2. Here, we use
multispecies sequence comparisons to identify a common SNP
(rs642961, G4A) in a newly identified IRF6 enhancer. The
A allele is significantly overtransmitted (P ¼ 1 1011) in
families with NSCL/P, in particular those with cleft lip but not
cleft palate. Further, there is a dosage effect of the A allele,
with a relative risk for cleft lip of 1.68 for the AG genotype
and 2.40 for the AA genotype. EMSA and ChIP assays
demonstrate that the risk allele disrupts the binding site of
transcription factor AP-2a and expression analysis in the
mouse localizes the enhancer activity to craniofacial and limb
structures. Our findings place IRF6 and AP-2a in the same
developmental pathway and identify a high-frequency variant
in a regulatory element contributing substantially to a
common, complex disorder