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    • Because conventional KO mice die within h of birth

    2020-03-21

    Because conventional KO mice die within 24h of birth, it is difficult to analyze higher H 89 functions using them. Therefore, in this study, we generated brain-specific conditional DGKδ-KO mice and used these mice to perform behavioral and pharmacological tests.
    Results
    Discussion OCD is a psychiatric affliction with a lifetime prevalence of 1–3% (Rasmussen and Eisen, 1992, Sasson et al., 1997). The essential features of OCD are recurrent obsessions and compulsions (e.g., doubting, checking and washing) that are time consuming or cause marked distress or significant impairment. For example, compulsive checking interferes with normal everyday functioning because of the many hours of time spent in the performance of checking rituals. OCD checking involves the performance of actions supposedly related to security, orderliness or accuracy, but is characterized by the repeated and excessive re-doing of such rituals. Several neural systems have been implicated in the pathophysiology of OCD. However, the nature of the dysfunction of the neurotransmitter systems postulated to be involved in OCD is still unknown. For obvious reasons, the understanding and treatment of diseases such as OCD must rely heavily on appropriate animal models that closely mimic their behavioral and, if possible, their neural manifestations (Joel, 2006). It is likely that the abnormal behaviors of the brain-specific DGKδ-KO mice are similar to OCD-like behaviors based on three criteria (Table 1): (1) ritualistic action to objects, (2) enhanced marble burying, and (3) sensitivity to a SSRI, fluoxetine. Although SSRIs are currently considered an effective first line treatment for OCD, there are some patients who do not respond to SSRI intervention (Fineberg et al., 2015). Therefore, the deficiency of DGKδ would provide a model for SSRI-sensitive OCD. SSRIs are also effective in several other psychiatric disorders, including depression, anxiety disorder and social phobia (Argyropoulos et al., 2000, Vaswani et al., 2003). However, the DGKδ-deficient mice did not show abnormal behaviors in the tail suspension test (anti-depressive activity) (Suppl. Fig. 9), the open field test (anxiety abnormalities) (Suppl. Fig. 4), the elevated plus-maze (anxiety abnormality) (Suppl. Fig. 5), or the sociability test (Suppl. Fig. 6). Therefore, it is unlikely that DGKδ is involved in those psychiatric disorders. There are several genetic mouse models of OCD (Joel, 2006). Greer and Capecchi reported that mice with disruptions of Hoxb8 show excessive grooming compared to control littermates (Greer and Capecchi, 2002). Chou-Green et al. reported that serotonin receptor 2c-KO mice showed increased chewing, but not eating, of non-nutritive clay and a tendency to exhibit increased chewing of a plastic screen (Chou-Green et al., 2003). Berridge et al. found that in addition to hyperactivity such as attention deficit hyperactivity disorder, the dopamine transporter-knockdown mice spent more time than wild-type mice engaged in grooming behavior (Berridge et al., 2005). Mice with a genetic deletion of SAP90/PSD95-associated protein 3 exhibited increased anxiety and compulsive grooming behavior leading to facial hair loss and skin lesions (Welch et al., 2007). Those phenotypes are different from those of the DGKδ-deficient mice. However, the etiology of OCD is currently unknown and most likely involves the interaction of multiple genetic and environmental factors (Murphy et al., 2001). Although we cannot deny the possibility that DGKδ is involved in other psychiatric disorders, the deficiencies of DGKδ, Hoxb8, serotonin receptor 2c, dopamine transporter, and SAP90/PSD95-associated protein 3 would provide models of different aspects of OCD. A female patient with a de novo balanced translocation, 46,X,t(X;2)(p11.2;q37)dn was found (Leach et al., 2007). In this patient, the DGKδ gene is disrupted at 2q37. This patient exhibited seizures. Although a potential seizure phenotype in mutant mice was investigated by a seizure-susceptibility study using PTZ, PTZ-induced seizures were not detected in the DGKδ-KO mice (Suppl. Fig. 3) as described previously (Leach et al., 2007). Mild self-harm such as skin-picking and hair-pulling was observed in the DGKδ-deficient patient (Leach et al., 2007). Interestingly, a relationship between self-harm and OCD was reported (Bejerot et al., 2014, Yaryura-Tobias et al., 1995), suggesting that the patient may have OCD-like disorders.