Abstract
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.
Highlights
Circadian rhythms are behavioral and physiological processes with a periodicity close to 24h generated by the suprachiasmatic nuclei (SCN), the circadian clock of the hypothalamus (Marcheva et al, 2013)
Here, we report that Shank3+/− mice did not show modifications in the circadian rhythm functioning, implying no alteration in the suprachiasmatic nucleus (SCN) physiology, as indicated by the lack of differences between groups in the circadian architecture: the tau was unaltered in DD, the durations of alpha and rho were similar between genotypes in entrained animals to either the long or short photoperiod, the re-entrainment to shifts in the L/D cycle, and in the skeleton photoperiod (SKP)
We found no evident differences between Shank3+/− and wild type (WT) mice in the immunohistochemical staining of the retinohypothalamic tract (RHT) projections and the NMDA receptor subunit 2A in SCN neurons
Summary
Circadian rhythms are behavioral and physiological processes with a periodicity close to 24h generated by the suprachiasmatic nuclei (SCN), the circadian clock of the hypothalamus (Marcheva et al, 2013). Glutamate activates N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AM PA)–kainate postsynaptic receptors (Kim and Dudek, 1991), which increase intracellular calcium in SCN neurons and activate signaling cascades necessary for the synchronization of the circadian clock to light (Ding et al, 1994, 1997). Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms of impaired communication and social interaction, repetitive or stereotyped behaviors, and altered sensory perception (Klintwall et al, 2011; Carbonetto, 2014; Baum et al, 2015; Bourgeron, 2015; Robertson and Baron-Cohen, 2017; Schroeder et al, 2017). One of the best characterized examples is Phelan–McDermid syndrome (PMS), which is caused by a deletion of the Shank gene in a single allele in the chromosome 22q13. SHANK3 scaffold ionotropic and metabotropic glutamate receptors are considered to be key regulators, either directly or indirectly, of synaptic transmission and plasticity (Monteiro and Feng, 2017)
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