scholarly journals Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders

2019 ◽  
Vol 20 (16) ◽  
pp. 3929 ◽  
Author(s):  
Fabian Dorninger ◽  
Anna Gundacker ◽  
Gerhard Zeitler ◽  
Daniela D. Pollak ◽  
Johannes Berger
Keyword(s):  
Psychiatric Disorders ◽  
Treatment Strategies ◽  
Ether Lipid ◽  
Detailed Examination ◽  
Behavioral Phenotype ◽  
Emotional Behavior ◽  
Mental Illnesses ◽  
Ether Lipids ◽  
Behavioral Abnormalities ◽  
Deficient Mice

Ether lipids form a specialized subgroup of phospholipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a mouse model. Here, we focused on a more detailed examination of the behavioral phenotype of ether lipid-deficient mice (Gnpat KO) and describe a set of features related to human psychiatric disorders. Gnpat KO mice show strongly impaired social interaction as well as nestlet shredding and marble burying, indicating disturbed execution of inborn behavioral patterns. Also, compromised contextual and cued fear conditioning in these animals suggests a considerable memory deficit, thus potentially forming a connection to the previously determined ether lipid deficit in human patients with Alzheimer’s disease. Nesting behavior and the preference for social novelty proved normal in ether lipid-deficient mice. In addition, we detected task-specific alterations in paradigms assessing depression- and anxiety-related behavior. The reported behavioral changes may be used as easy readout for the success of novel treatment strategies against ether lipid deficiency in ameliorating nervous system-associated symptoms. Furthermore, our findings underline that ether lipids are paramount for brain function and demonstrate their relevance for cognitive, social, and emotional behavior. We hereby substantially extend previous observations suggesting a link between deficiency in ether lipids and human mental illnesses, particularly autism and attention-deficit hyperactivity disorder.

scholarly journals Unequivocal mapping of molecular ether lipid species by LC-MS/MS in plasmalogen-deficient mice

2020 ◽  
Author(s):  
Jakob Koch ◽  
Katharina Lackner ◽  
Yvonne Wohlfarter ◽  
Sabrina Sailer ◽  
Johannes Zschocke ◽  
...  
Keyword(s):  
Ether Lipid ◽  
Mental Disability ◽  
Facial Dysmorphism ◽  
Chondrodysplasia Punctata ◽  
Ether Lipids ◽  
Rhizomelic Chondrodysplasia Punctata ◽  
Lipid Species ◽  
Wide Range ◽  
Complex Lipid ◽  
Deficient Mice

AbstractDeficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability. Mouse models are available but show less severe symptoms. In both humans and mice it has remained elusive which of the symptoms can be attributed to lack of plasmanyl or plasmenyl ether lipids. The latter compounds, better known as plasmalogens, harbor a vinyl ether double bond conferring special chemical and physical properties. Discrimination between plasmanyl and plasmenyl ether lipids is a major analytical challenge, especially in complex lipid extracts with many isobaric species. Consequently, these lipids are often neglected also in recent lipidomic studies. Here we present a comprehensive LC-MS/MS based approach that allows unequivocal distinction of these two lipid subclasses based on their chromatographic properties. The method was validated using a novel plasmalogen-deficient mouse model which lacks plasmanylethanolamine desaturase and therefore cannot form plasmenyl ether lipids. We demonstrate that plasmanylethanolamine desaturase deficiency causes an accumulation of plasmanyl species, a little studied but biologically important substance class.

scholarly journals Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

2021 ◽  
Vol 13 ◽  
Author(s):  
Ryan D. Shepard ◽  
Fereshteh S. Nugent
Keyword(s):  
Psychiatric Disorders ◽  
Life Stress ◽  
Early Life ◽  
Neural Circuits ◽  
Treatment Strategies ◽  
Early Life Stress ◽  
Mental Illnesses ◽  
Lateral Habenula ◽  
Psychiatric Illnesses ◽  
New Research

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.

scholarly journals Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Freddy Zhang ◽  
Benjamin Rein ◽  
Ping Zhong ◽  
Treefa Shwani ◽  
Megan Conrow-Graham ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Social Preference ◽  
Intervention Strategy ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Male Mice ◽  
Behavioral Abnormalities ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3–5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.

Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior

2017 ◽  
Vol 18 (12) ◽  
pp. 1342-1352 ◽  
Author(s):  
Michio Miyajima ◽  
Baihao Zhang ◽  
Yuki Sugiura ◽  
Kazuhiro Sonomura ◽  
Matteo M Guerrini ◽  
...  
Keyword(s):  
T Cells ◽  
Emotional Behavior ◽  
Metabolic Shift ◽  
Brain Monoamines ◽  
Deficient Mice

scholarly journals Severe persistent mental illness

1992 ◽  
Vol 16 (12) ◽  
pp. 743-745 ◽  
Author(s):  
Peter F. Liddle
Keyword(s):  
Mental Illness ◽  
Mental Hospital ◽  
Community Care ◽  
Community Setting ◽  
Detailed Examination ◽  
Mental Illnesses ◽  
Persistent Mental Illness ◽  
Realistic Appraisal

Many patients with persistent mental illnesses enjoy a better life in a community setting than would be possible in a long stay mental hospital. Furthermore, the available evidence indicates that most such patients get better while living in the community. Unfortunately, community care has not served all patients well. Much of the difficulty can be attributed to lack of resources. However, there is also a tendency by planners to underestimate the severity of patients' disabilities. A realistic appraisal demands a detailed examination of the problems of patients whose needs have not been met by community care. One important issue is that of patients who fall through the net of community care and another is that of patients who have not but nonetheless have not survived in the community. This paper addresses the question of the needs of this latter group.

scholarly journals Juvenile Shank3b deficient mice present with behavioral phenotype relevant to autism spectrum disorder

2019 ◽  
Vol 356 ◽  
pp. 137-147 ◽  
Author(s):  
Chantell Balaan ◽  
Michael J. Corley ◽  
Tiffany Eulalio ◽  
Ka’ahukane Leite-ahyo ◽  
Alina P.S. Pang ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Behavioral Phenotype ◽  
Spectrum Disorder ◽  
Deficient Mice

scholarly journals Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice

2017 ◽  
Vol 312 (1) ◽  
pp. C16-C28 ◽  
Author(s):  
D. Randazzo ◽  
B. Blaauw ◽  
C. Paolini ◽  
E. Pierantozzi ◽  
S. Spinozzi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Detailed Examination ◽  
Diaphragm Muscle ◽  
Hindlimb Muscles ◽  
Skeletal Muscle Fibers ◽  
Exercise Induced ◽  
Old Mice ◽  
Ankyrin B ◽  
Deficient Mice

We recently reported that skeletal muscle fibers of obscurin knockout (KO) mice present altered distribution of ankyrin B (ankB), disorganization of the subsarcolemmal microtubules, and reduced localization of dystrophin at costameres. In addition, these mice have impaired running endurance and increased exercise-induced sarcolemmal damage compared with wild-type animals. Here, we report results from a combined approach of physiological, morphological, and structural studies in which we further characterize the skeletal muscles of obscurin KO mice. A detailed examination of exercise performance, using different running protocols, revealed that the reduced endurance of obscurin KO animals on the treadmill depends on exercise intensity and age. Indeed, a mild running protocol did not evidence significant differences between control and obscurin KO mice, whereas comparison of running abilities of 2-, 6-, and 11-mo-old mice exercised at exhaustion revealed a progressive age-dependent reduction of the exercise tolerance in KO mice. Histological analysis indicated that heavy exercise induced leukocyte infiltration, fibrotic connective tissue deposition, and hypercontractures in the diaphragm of KO mice. On the same line, electron microscopy revealed that, in the diaphragm of exercised obscurin KO mice, but not in the hindlimb muscles, both M-line and H-zone of sarcomeres appeared wavy and less defined. Altogether, these results suggest that obscurin is required for the maintenance of morphological and ultrastructural integrity of skeletal muscle fibers against damage induced by intense mechanical stress and point to the diaphragm as the skeletal muscle most severely affected in obscurin-deficient mice.

scholarly journals Coercive Measures and Stigmatization in the Psychiatric Medical Care

2020 ◽  
Vol 11 (3sup1) ◽  
pp. 137-145
Author(s):  
Petronela Nechita ◽  
◽  
Liliana Luca ◽  
Alina-Ioana Voinea ◽  
Codrina Moraru ◽  
...  
Keyword(s):  
Mental Health ◽  
Psychiatric Disorders ◽  
Psychiatric Hospital ◽  
Treatment Compliance ◽  
Mental Illnesses ◽  
Internal Conflict ◽  
Involuntary Admission ◽  
Coercive Measures ◽  
Self Harm ◽  
The Law

The involuntary commitment of psychiatric patients has been done for almost a decade under the Law 487/2002, the law of mental health and protection for people with psychiatric disorders. Frequent involuntary psychiatric hospitalizations have led to stigma attitudes and discriminatory acts towards patients with mental disorders. The coercive medical measures are applied in the psychiatric institutions of the mental health protection agencies. Coercion gives rise to serious ethical debates in the psychiatric assistance. The individual who was hospitalized in a psychiatric hospital anticipates social rejection becoming defensive, withdraws socially, experiences a complex internal conflict. The goal for this study is to illustrate aspects linked to coercive measures, mechanical restraint at involuntary admission of patients with mental illnesses in the psychiatric medical assistance. Material and method: This study is a retrospective one, and the data was taken from the charts with involuntary admissions during the period of October 2002 to July 2012. The studied lot was comprised of 202 patients admitted involuntarily in a psychiatric hospital according to the Law 487/2002, the law of mental health and protection for people with psychiatric disorders. Results: Of the 25.7% patients admitted involuntarily, that required coercive measures during admission, 58% were contained for symptoms like self-harm. The mechanical contention measures were especially necessary in the acute cases with symptoms as self-harm and/or harm of others, but also in situations with hallucinatory-delirium symptoms. The ratio of male sex subjects was significantly higher in the subject lot that needed coercive measures during hospitalization, of those admitted involuntarily (86.5% vs. 72%) (p = 0.036). Conclusions: Involuntary admission and mandatory treatment remains in psychiatry a medical, legal and ethical problem. The required measures can lead mainly to clinical benefits, implying a paternal attitude from the psychiatry specialists by defying the patients’ autonomy. Treatment compliance is directly proportional to the overall level of functioning and inversely proportional to the level of self-stigmatization.

scholarly journals Reduced muscle strength in ether lipid-deficient mice is accompanied by altered development and function of the neuromuscular junction

2017 ◽  
Vol 143 (5) ◽  
pp. 569-583 ◽  
Author(s):  
Fabian Dorninger ◽  
Ruth Herbst ◽  
Bojana Kravic ◽  
Bahar Z. Camurdanoglu ◽  
Igor Macinkovic ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Neuromuscular Junction ◽  
Ether Lipid ◽  
And Function ◽  
Deficient Mice
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