Polymorphisms in the oxytocin receptor and their association with apathy and impaired social cognition in Huntington’s disease

Saiz‐Rodríguez, Miriam; Gil‐Polo, Cecilia; Díez-Fairén, Mónica; Martinez-Horta, Saul-Indra; Sampedro, Frederic; Calvo, Sara; Alonso-García, Esther; Riñones-Mena, Esther; Aguado, Laura; Mariscal, Natividad; Muñoz-Siscart, Ignacio; Piñeiro, Dolores; Rivadeneyra, J; Cubo, Esther

doi:10.1007/s10072-022-06226-1

Cited by 4 publications

(6 citation statements)

References 10 publications

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“…44,45 Genetic variations of OXTR have recently been shown to influence the prevalence of social impairment in HD patients. 46 The effects of manipulation of mHTT expression in OXTRexpressing neurons would, therefore, be interesting to explore.…”

Section: Discussionmentioning

confidence: 99%

“…OXT receptors (OXTRs) have been found in many other brain regions of the limbic system involved in emotional control and cognition, including the amygdala and prefrontal cortex 44,45 . Genetic variations of OXTR have recently been shown to influence the prevalence of social impairment in HD patients 46 . The effects of manipulation of mHTT expression in OXTR‐expressing neurons would, therefore, be interesting to explore.…”

Section: Discussionmentioning

confidence: 99%

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Effects of mutant huntingtin in oxytocin neurons on non‐motor features of Huntington's disease

Bergh

Gabery

Tonetto

et al. 2023

Neuropathology Appl Neurobio

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Background Early non‐motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non‐motor features and neuropathology. Methods To express mHTT only in OXT neurons, we used a novel flex‐switch adeno‐associated viral vector design to selectively express either mHTT or wild‐type HTT in the paraventricular nucleus of the hypothalamus using OXT‐Cre‐recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post‐injection or at 2 months of age, respectively. Post‐mortem analyses were performed to assess the effects on the OXT system. Results Our results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT‐immunopositive neurons as well as increased anxiety‐like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point. Conclusions Our results indicate that mHTT expression can exert cell‐autonomous toxic effects on OXT neurons without affecting the non‐motor phenotype at early time points in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of mutant huntingtin in oxytocin neurons on non‐motor features of Huntington's disease

Bergh

Gabery

Tonetto

et al. 2023

Neuropathology Appl Neurobio

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“…In a previous study, we found a possible association between apathy and impaired social cognition and some polymorphisms in the oxytocin receptor coding gene ( OXTR ) that might be some evidence of hypothalamic degeneration in HD, leading to oxytocinergic dysfunction in HD and its association with neuropsychiatric manifestations [ 93 ]. Polymorphisms in the oxytocin receptor could have a relevant role in the correct development of social and cognitive functions.…”

Section: Other Biomarkers In Studymentioning

confidence: 99%

“…Polymorphisms in the oxytocin receptor could have a relevant role in the correct development of social and cognitive functions. We found various OXTR -synonymous variants that warrant further study for their involvement in apathy, irritability, and social cognition in HD [ 93 ].…”

Section: Other Biomarkers In Studymentioning

confidence: 99%

Pharmacogenetics in the Treatment of Huntington’s Disease: Review and Future Perspectives

García-González

Cubo

Simón-Vicente

et al. 2023

JPM

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Huntington’s disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease. HD is still a complex condition in need of innovative and efficient treatment. The long-term goal of pharmacogenetic studies is to use genotype data to predict the effective treatment response to a specific drug and, in turn, prevent potential undesirable effects of its administration. Chorea, depression, and psychotic symptoms have a substantial impact on HD patients’ quality of life and could be better controlled with the help of pharmacogenetic knowledge. We aimed to carry out a review of the available publications and evidence related to the pharmacogenetics of HD, with the objective of compiling all information that may be useful in optimizing drug administration. The impact of pharmacogenetic information on the response to antidepressants and antipsychotics is well documented in psychiatric patients, but this approach has not been investigated in HD patients. Future research should address several issues to ensure that pharmacogenetic clinical use is appropriately supported, feasible, and applicable.

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“…Interestingly, in a recent study, distinct OXTR expression patterns have been shown in psychiatric disorders as well as in metabolic regulation processes across development in humans ( Rokicki et al, 2022 ). Furthermore, genetic variation of OXTR has also been shown to be associated with social impairment in HD ( Saiz-Rodríguez et al, 2022 ). When exogenously administered, OXT facilitates social encounters, improved social cognitive outcomes as well as emotion recognition in healthy and clinical groups characterized by social deficits, such as autism and social anxiety disorder ( Heinrichs et al, 2009 ; Keech et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Oxytocin in Huntington’s disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia

Bergh

Cheong

Petersén

et al. 2022

Front. Mol. Neurosci.

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Neurodegenerative disorders (NDDs) such as Huntington’s disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human post-mortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs.

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Polymorphisms in the oxytocin receptor and their association with apathy and impaired social cognition in Huntington’s disease

Cited by 4 publications

References 10 publications

Effects of mutant huntingtin in oxytocin neurons on non‐motor features of Huntington's disease

Effects of mutant huntingtin in oxytocin neurons on non‐motor features of Huntington's disease

Pharmacogenetics in the Treatment of Huntington’s Disease: Review and Future Perspectives

Oxytocin in Huntington’s disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia

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