RESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in communication and social interaction, repetitive or stereotypical behaviors, altered sensory perception, and sleep disorders. In general, the causes of ASD remain unknown, but in Phelan-McDermid syndrome, it is known that the disorder is related to the haploinsufficiency of the Shank3 gene. We used an autism model with compromised glutamatergic signaling, the Shank3+/- mouse, to study the circadian rhythm architecture of locomotion behavior and its entrainment to light. We also analyzed the synapse between the retinohypothalamic tract (RHT) and the suprachiasmatic nucleus (SCN), employing tract tracing and immunohistochemical techniques. We found that Shank3+/- mice were not impaired in the SCN circadian clock, as indicated by a lack of differences between groups in the circadian architecture in entrained animals to either long or short photoperiods. Circadian rhythm periodicity (tau) was unaltered between genotypes in constant darkness (DD, dim red light). Similar results were obtained in the re-entrainment to shifts in the light-dark cycle and in the entrainment to a skeleton photoperiod from DD. However, Shank3+/- mice showed larger phase responses to light pulses, both delays and advances, and rhythm disorganization induced by constant bright light. Immunohistochemical analyses indicated no differences in the RHT projection to the SCN or the number of SCN neurons expressing the N-methyl-D-aspartate (NMDA) receptor subunit NR2A, whereas the Shank3+/- animals showed decreased c-Fos induction by brief light pulses at CT14, but increased number of vasoactive intestinal polypeptide (VIP)-positive neurons. These results indicate alterations in light sensitivity in Shank3+/- mice. Further studies are necessary to understand the mechanisms involved in such increased light sensitivity, probably involving VIP neurons.
RESUMEN
Calcium-regulated chloride channel (CaCC) anoctamin-1 has been recently identified in neurons. In neurons, which express the Na-K-2Cl cotransporter, activation of CaCCs increases firing frequency, by reversion between the Cl equilibrium potential and the membrane resting potential, leading to membrane depolarization by Cl extrusion from the cell. Although there are no reports of CaCCs present in the suprachiasmatic nuclei (SCN), the fact that Na-K-2Cl cotransporter is present in SCN neurons, where it has been shown to be involved in the excitatory effects of γ-aminobutyric acid, together with the increase of neuronal firing rate induced by release of intracellular Ca after administration of 100 nM ryanodine, leads us to determine whether CaCCs are present in the SCN. Immunohistochemistry and western blots show the expression of the CaCCs anoctamin-1 protein. Quantitative PCR demonstrated the expression of anoctamin-1 mRNA in the SCN. These results clearly indicate the presence of CaCC in SCN of rats.