DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.

Step in Time: Conservation of Circadian Clock Genes in Animal Evolution.

Over the past few decades, the molecular mechanisms responsible for circadian phenotypes of animals have been studied in increasing detail in mammals, some insects, and other invertebrates. Particular circadian proteins and their interactions are shared across evolutionary distant animals, resulting in a hypothesis for the canonical circadian clock of animals. As the number of species for which the circadian clockwork has been described increases, the circadian clock in animals driving cyclical phenotypes becomes less similar. Our focus in this review is to develop and synthesize the current literature to better understand the antiquity and evolution of the animal circadian clockwork. Here, we provide an updated understanding of circadian clock evolution in animals, largely through the lens of conserved genes characterized in the circadian clock identified in bilaterian species. These comparisons reveal extensive variation within the likely composition of the core clock mechanism, including losses of many genes, and that the ancestral clock of animals does not equate to the bilaterian clock. Despite the loss of these core genes, these species retain circadian behaviors and physiology, suggesting novel clocks have evolved repeatedly. Additionally, we highlight highly conserved cellular processes (e.g., cell division, nutrition) that intersect with the circadian clock of some animals. The conservation of these processes throughout the animal tree remains essentially unknown, but understanding their role in the evolution and maintenance of the circadian clock will provide important areas for future study.

The Molecular Clock and Neurodegenerative Disease: A Stressful Time.

Circadian rhythm dysfunction occurs in both common and rare neurodegenerative diseases. This dysfunction manifests as sleep cycle mistiming, alterations in body temperature rhythms, and an increase in symptomatology during the early evening hours known as Sundown Syndrome. Disruption of circadian rhythm homeostasis has also been implicated in the etiology of neurodegenerative disease. Indeed, individuals exposed to a shifting schedule of sleep and activity, such as health care workers, are at a higher risk. Thus, a bidirectional relationship exists between the circadian system and neurodegeneration. At the heart of this crosstalk is the molecular circadian clock, which functions to regulate circadian rhythm homeostasis. Over the past decade, this connection has become a focal point of investigation as the molecular clock offers an attractive target to combat both neurodegenerative disease pathogenesis and circadian rhythm dysfunction, and a pivotal role for neuroinflammation and stress has been established. This review summarizes the contributions of molecular clock dysfunction to neurodegenerative disease etiology, as well as the mechanisms by which neurodegenerative diseases affect the molecular clock.