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The N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis has been proposed to help understand the etiology and pathophysiology of schizophrenia. This hypothesis was based on early observations that NMDAR antagonists could induce a full range of symptoms of schizophrenia in normal human subjects. Accumulating evidence in humans and animal studies points to NMDAR hypofunctionality as a convergence point for various symptoms of schizophrenia. Here we review animal models of NMDAR hypofunction generated by pharmacological and genetic approaches, and how they relate to the pathophysiology of schizophrenia. In addition, we discuss the limitations of animal models of NMDAR hypofunction and their potential utility for therapeutic applications.

One of the core pathogenic mechanisms for schizophrenia is believed to be dysfunction in glutamatergic synaptic transmissions, particularly hypofunction of N-methyl d-aspartate receptors (NMDARs). Previously we showed that 14-3-3 functional knockout mice exhibit schizophrenia-associated behaviors accompanied by reduced synaptic NMDARs in forebrain excitatory neurons. To investigate how 14-3-3 proteins regulate synaptic localization of NMDARs, here we examined changes in levels of synaptic NMDARs upon 14-3-3 inhibition in primary neurons. Expression of 14-3-3 protein inhibitor (difopein) in primary glutamatergic cortical and hippocampal neurons resulted in lower number of synaptic puncta containing NMDARs, including the GluN1, GluN2A, or GluN2B subunits. In heterologous cells, 14-3-3 proteins enhanced surface expression of these NMDAR subunits. Furthermore, we identified that 14-3-3ζ and ε isoforms interact with NMDARs via binding to GluN2A and GluN2B subunits. Taken together, our results demonstrate that 14-3-3 proteins play a critical role in NMDAR synaptic trafficking by promoting surface delivery of NMDAR subunits GluN1, GluN2A, and GluN2B. As NMDAR hypofunctionality is known to act as a convergence point for progression of symptoms of schizophrenia, further studies on these signaling pathways may help understand how dysfunction of 14-3-3 proteins can cause NMDAR hypofunctionality and lead to schizophrenia-associated behaviors.

The seven mammalian isoforms of 14-3-3 are each encoded by a unique gene and function as phosphorylation dependent protein modulators. Because 14-3-3 proteins have particularly high expression in the brain, they have been implicated in a variety of neuronal functions. Recently, we showed that functional knockout of all 14-3-3 isoforms in forebrain glutamatergic neurons of mice is sufficient to induce schizophrenia-like endophenotypes. Human and animal studies have linked mutations in Ywhae and 14-3-3ε expression changes to certain neurodevelopmental and psychiatric diseases. In this study, we conditionally knocked out 14-3-3ε from forebrain glutamatergic neurons by crossing Ywhae flox/flox mice with CaMKIIα-Cre mice. Ywhae flox/flox Cre + (conditional knockout -CKO) mice and their Ywhae flox/flox Cre - (double-flox control - dFlC) littermates were put through a battery of behavioral tests to assess their behavioral endophenotypes. Ywhae CKO mice exhibited significant differences from dFlC mice in some of the behaviors examined. We also found several significant sex differences within our model. Furthermore, we compared two viral 14-3-3 knockout methods and found that CaMKIIα promoter driven difopein expression in wildtype mice is more efficient than Cre/loxP driven difopein expression in CaMKIIα-Cre mice. Collectively our results indicate that knocking out 14-3-3ε in glutamatergic forebrain neurons via this strategy is not sufficient to induce schizophrenia-like behavioral alterations. In the future, using different mouse line or knockout scheme may help further elucidate the isoform specific role of 14-3-3ε in the forebrain.

Both Fyn and tau have been associated with neuronal hyperexcitability and neurotoxicity in many tauopathies, including Alzheimer's disease (AD). Individual genetic ablation of fyn or tau appears to be protective against aberrant excitatory neuronal activities in AD and epilepsy models. It is, however, still unknown whether ablation of both Fyn and tau can likely elicit more profound anti-seizure and neuroprotective effects. Here, we show the effects of genetic deletion of Fyn and/or tau on seizure severity in response to pentylenetetrazole (PTZ)-induced seizure in mouse models and neurobiological changes 24 h post-seizures. We used Fyn KO ( fyn −/− ), tau KO ( tau −/− ), double knockout (DKO) ( fyn −/− / tau −/− ), and wild-type (WT) mice of the same genetic background. Both tau KO and DKO showed a significant increase in latency to convulsive seizures and significantly decreased the severity of seizures post-PTZ. Although Fyn KO did not differ significantly from WT, in response to PTZ, Fyn KO still had 36 ± 8% seizure reduction and a 30% increase in seizure latency compared to WT. Surprisingly, in contrast to WT, Fyn KO mice showed higher mortality in <20 min of seizure induction; these mice had severe hydrocephalous. None of the tau −/− and DKO died during the study. In response to PTZ, all KO groups showed a significant reduction in neurodegeneration and gliosis, in contrast to WT, which showed increased neurodegeneration [especially, parvalbumin (PV)-GABAergic interneurons] and gliosis. DKO mice had the most reduced gliosis. Immunohistochemically, phospho-tau (AT8, pS199/S202), Fyn expression, as well as Fyn-tau interaction as measured by PLA increased in WT post-PTZ. Moreover, hippocampal Western blots revealed increased levels of AT8, tyrosine phospho-tau (pY18), and phosphorylated Src tyrosine family kinases (pSFK) in PTZ-treated WT, but not in KO, compared to respective controls. Furthermore, PV interneurons were protected from PTZ-induced seizure effects in all KO mice. The levels of inwardly rectifying potassium (Kir 4.1) channels were also downregulated in astrocytes in the WT post-PTZ, while its levels did not change in KO groups. Overall, our results demonstrated the role of Fyn and tau in seizures and their impact on the mediators of early epileptogenesis in PTZ model.

One of the core pathogenic mechanisms for schizophrenia is believed to be dysfunction in glutamatergic synaptic transmissions, particularly hypofunction of N-methyl d-aspartate receptors (NMDARs). Previously we showed that 14-3-3 functional knockout mice exhibit schizophrenia-associated behaviors accompanied by reduced synaptic NMDARs in forebrain excitatory neurons. To investigate how 14-3-3 proteins regulate synaptic localization of NMDARs, here we examined changes in levels of synaptic NMDARs upon 14-3-3 inhibition in primary neurons. Expression of 14-3-3 protein inhibitor (difopein) in primary glutamatergic cortical and hippocampal neurons resulted in lower number of synaptic puncta containing NMDARs, including the GluN1, GluN2A, or GluN2B subunits. In heterologous cells, 14-3-3 proteins enhanced surface expression of these NMDAR subunits. Furthermore, we identified that 14-3-3[zeta] and [epsilon] isoforms interact with NMDARs via binding to GluN2A and GluN2B subunits. Taken together, our results demonstrate that 14-3-3 proteins play a critical role in NMDAR synaptic trafficking by promoting surface delivery of NMDAR subunits GluN1, GluN2A, and GluN2B. As NMDAR hypofunctionality is known to act as a convergence point for progression of symptoms of schizophrenia, further studies on these signaling pathways may help understand how dysfunction of 14-3-3 proteins can cause NMDAR hypofunctionality and lead to schizophrenia-associated behaviors.

This study investigated the role of acceptance during the transition process among autistic young adults, parents, and practitioners. Six focus groups were run and thematic analysis was used to identify four themes: Youth on the autism spectrum discussed transition as a time where Self-Advocacy and Self-Acceptance were salient. Both youth and parents discussed the Lack of Understanding and Acceptance they experience. Particularly, youth highlighted the lack of understanding of sensory needs and parents underscored the lack of understanding by medical professionals. In contrast, practitioners highlighted the presence of Community Openness. Both practitioners and parents discussed Finding Personal Support through Acceptance. Self-acceptance and acceptance of autism are imperative for autistic young adults and families to achieve well-being.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that is characterized by impact on individuals’ socialization, communication, and behavior. The transition to adulthood can be challenging for many autistic emerging adults and their families considering the core clinical characteristics of ASD, limited social support, and lack of resources. Taken together these challenges make the transition process difficult and may yield undesirable adult outcomes. The current study examines how the process of transitioning to adulthood impacts families. We conducted six focus group interviews with autistic emerging adults ( n  = 6), parents of autistic transitional age youth (TAY) ( n  = 7), and transition related practitioners ( n  = 11). Thematic analysis was used to identify four themes. Autistic emerging adults described Redefining Meaningful Interpersonal Relationships as a salient domain of the transition experience. Parents discussed Being Overwhelmed by Demands and Uncertainty that Leads to Anxiety . Practitioners discussed Parents’ Lack of Readiness –that some parents may have difficulty receiving input from practitioners regarding the transition process. Our findings indicate that emerging adults’ social relationships are greatly impacted during the transition to adulthood. Parents need more support as their autistic child transitions to adulthood to best assist their child and for their own mental health. Practitioners acknowledge the importance of parents’ evolving roles during the transition process. Highlight The period of transitioning to adulthood was not only impactful for autistic emerging adults but also for parents. Whereas autistic emerging adults focused on normative developmental tasks, it was a time of anxiety for parents. Practitioners had concerns that some parents were not prepared for their child’s transition to adulthood. The transition process can be influenced by support and education for caregiving families.

The purpose of this study is to develop a mouse sperm preservation method based on evaporative drying. Mouse sperm were evaporatively dried and stored at 4°C and ambient temperature for 3 months to 2 years. Upon rehydration, a single sperm was injected into a mature oocyte to develop into a blastocyst after culture or a live birth after embryo transfer to a recipient female. For the samples stored at 4°C for 3, 6, 12, 18, and 24 months, the blastocyst formation rate was 61.5%, 49.1%, 31.5%, 32.2%, and 41.4%, respectively. The blastocyst rate for those stored at ambient temperature (∼22°C) for 3, 6, 12, and 18 months was 57.8%, 36.2%, 33.6%, and 34.4%, respectively. Fifteen, eight and three live pups were produced from sperm stored at room temperature for 12, 18, and 24 months, respectively. This is the first report of live offspring produced from dried mouse sperm stored at ambient temperature for up to 2 years. Based on these results, we suggest that evaporative drying is a potentially useful method for the routine preservation of mouse sperm.

Background/Objectives: Research suggests that attitudes toward aging significantly impact health and well-being outcomes in older adults and are influenced by various factors. Our study aims to identify gender differences in attitudes toward aging among aging individuals with disabilities while also examining the influence of demographic and psychological factors on these attitudes. Methods: For this cross-sectional study, we collected data from 393 middle-aged and older adults with disabilities via an online Qualtrics survey administered through the Prolific platform in the United States. Participants completed the Attitudes Towards Aging Questionnaire Short Form, Purpose in Life Test Short Form, Mindfulness Attention Awareness Scale, Acceptance of Chronic Health Conditions Scale, and Three-Item Loneliness Scale. Descriptive and correlation analyses, t-tests, and multiple regression analyses were performed. Results: The independent t-test findings reveal significant differences in physical change and psychological growth between men and women, with men scoring higher in physical change and women in psychological growth. In multiple regression analyses, purpose in life significantly predicted all three domains of attitudes toward aging in men, while both purpose in life and acceptance were predictors across all domains in women. Additionally, age, employment, and financial stability contributed to aging attitudes only among women. Conclusions: Attitudes toward aging, specifically physical change and psychological growth, were found to vary by gender, with purpose in life, acceptance, and loneliness influencing these attitudes among both groups, while certain demographic factors influenced aging attitudes only among women. These findings underscore the need for gender-specific interventions addressing these substantial factors.