Background and Hypothesis Schizophrenia is associated with altered energy metabolism, but the cause and potential impact of these metabolic changes remain unknown. 22q11.2 deletion syndrome (22q11.2DS) represents a genetic risk factor for schizophrenia, which is associated with the loss of several genes involved in mitochondrial physiology. Here we examine how the haploinsufficiency of these genes could contribute to the emergence of schizophrenia in 22q11.2DS. Study Design We characterize changes in neuronal mitochondrial function caused by haploinsufficiency of mitochondria-associated genes within the 22q11.2 region (PRODH, MRPL40, TANGO2, ZDHHC8, SLC25A1, TXNRD2, UFD1, and DGCR8). For that purpose, we combine data from 22q11.2DS carriers and schizophrenia patients, in vivo (animal models) and in vitro (induced pluripotent stem cells, IPSCs) studies. We also review the current knowledge about seven non-coding microRNA molecules located in the 22q11.2 region that may be indirectly involved in energy metabolism by acting as regulatory factors. Study Results We found that the haploinsufficiency of genes of interest is mainly associated with increased oxidative stress, altered energy metabolism, and calcium homeostasis in animal models. Studies on IPSCs from 22q11.2DS carriers corroborate findings of deficits in the brain energy metabolism, implying a causal role between impaired mitochondrial function and the development of schizophrenia in 22q11.2DS. Conclusions The haploinsufficiency of genes within the 22q11.2 region leads to multifaceted mitochondrial dysfunction with consequences to neuronal function, viability, and wiring. Overlap between in vitro and in vivo studies implies a causal role between impaired mitochondrial function and the development of schizophrenia in 22q11.2DS. 22q11.2 deletion syndrome leads to changes in energy metabolism: Lower ATP levels, enhanced glycolysis and decreased OXPHOS rates, decreased antioxidant capacity, and aberrant calcium homeostasis. Although 22q11.2DS is the strongest single genetic risk factor for schizophrenia development, prenatal or postnatal insults (as indicated by the second hit) are necessary for schizophrenia to develop
There is a pressing need for an ecologically relevant behavioral task that would enable the study of elementary aspects of episodic memory. In everyday life, episodic memories are acquired incidentally in a single-encounter fashion and are composed of sub-events separated by time gaps. We designed a behavioral task called One-Trial Trace Escape Reaction (OTTER), in which rats incidentally associated two temporally discontinuous stimuli. In OTTER, rats associate a neutral acoustic cue (conditioned stimulus, CS) with an aversive stimulus (unconditioned stimulus, US) which occurs two seconds later: we call this sequence CS-2s-US. In the first few sessions, rats are habituated to two similar environmental contexts (A and B); each context consists of interconnected dark and light sub-areas. Next, in the pairing session, rats experience CS-2s-US in the dark sub-area of one of the environmental contexts (either A or B). The US is terminated immediately after a rat escapes into the light sub-area. During the recall session 24 hours later, rats are presented with only the CS in the alternate environmental context (B or A) and their behavioral response is observed. Our results show that 50% of handled rats and 14% of non-handled rats responded to the CS by escaping to the light sub-area although they experienced only a single CS-2s-US pairing. The capacity to acquire a CS-2s-US association in a single CS-2s-US pairing indicates that rodents are able to form incidental temporal associations. The OTTER behavioral task offers a flexible high throughput tool to study memories acquired incidentally after a single experience.
We designed a behavioral task called One-Trial Trace Escape Reaction (OTTER), in which rats incidentally associate two temporally discontinuous stimuli: a neutral acoustic cue (CS) with an aversive stimulus (US) which occurs two seconds later (CS-2s-US sequence). Rats are first habituated to two similar environmental contexts (A and B), each consisting of an interconnected dark and light chamber. Next, rats experience the CS-2s-US sequence in the dark chamber of one of the contexts (either A or B); the US is terminated immediately after a rat escapes into the light chamber. The CS-2s-US sequence is presented only once to ensure the incidental acquisition of the association. The recall is tested 24 h later when rats are presented with only the CS in the alternate context (B or A), and their behavioral response is observed. Our results show that 59 % of the rats responded to the CS by escaping to the light chamber, although they experienced only one CS-2s-US pairing. The OTTER task offers a flexible high throughput tool to study memory acquired incidentally after a single experience. Incidental acquisition of association between temporally discontinuous events is highly relevant to episodic memory formation.
We designed a behavioral task called One-Trial Trace Escape Reaction (OTTER), in which rats incidentally associate two temporally discontinuous stimuli: a neutral acoustic cue (CS) with an aversive stimulus (US) which occurs two seconds later (CS-2s-US sequence). Rats are first habituated to two similar environmental contexts (A and B), each consisting of an interconnected dark and light chamber. Next, rats experience the CS-2s-US sequence in the dark chamber of one of the contexts (either A or B); the US is terminated immediately after a rat escapes into the light chamber. The CS-2s-US sequence is presented only once to ensure the incidental acquisition of the association. The recall is tested 24 h later when rats are presented with only the CS in the alternate context (B or A), and their behavioral response is observed. Our results show that 59% of the rats responded to the CS by escaping to the light chamber, although they experienced only one CS-2s-US pairing. The OTTER task offers a flexible high throughput tool to study memory acquired incidentally after a single experience. Incidental one-trial acquisition of association between temporally discontinuous events may be one of the essential components of episodic memory formation.
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