Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning

Long-term depression (LTD) of AMPA-type glutamate receptor (AMPA receptor)-mediated synaptic transmission has been proposed as a cellular substrate for learning and memory. Although activity-induced AMPA receptor endocytosis is believed to underlie LTD, it remains largely unclear whether LTD and AMPA receptor endocytosis at specific synapses are causally linked to learning and memory in vivo. Here we developed a new optogenetic tool, termed PhotonSABER, which enabled the temporal, spatial, and cell-type-specific control of AMPA receptor endocytosis at active synapses, while the basal synaptic properties and other forms of synaptic plasticity were unaffected. We found that fiberoptic illumination to Purkinje cells expressing PhotonSABER in vivo inhibited cerebellar motor learning during adaptation of the horizontal optokinetic response and vestibulo-ocular reflex, as well as synaptic AMPA receptor decrease in the flocculus. Our results demonstrate that LTD and AMPA receptor endocytosis at specific neuronal circuits were directly responsible for motor learning in vivo

Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors.

The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities

Association between decrease in frequency of going out and oral function in older adults living in major urban areas

Aim To examine the association between a decrease in the frequency of going out and oral function in independent older adults living in the urban area of Tokyo. Methods The participants analyzed were 785 older adults from the "Takashimadaira Study" (344 men and 441 women, age 77.0 +/- 4.6 years). This study investigated the following items: decrease in frequency of going out; basic characteristics (sex, age); physical factors, such as oral function (difficulty chewing, difficulty swallowing, dry mouth); body pain; the Japan Science and Technology Agency Index of Competence; physical activities; psychological factors, such as the Geriatric Depression Scale-15 score; and social and environmental factors, such as the presence or absence of participation in organization activities. Results To investigate the factors associated with a decrease in frequency of going out, logistic regression analysis showed an association with age (OR 1.08, 95% CI 1.03-1.13), difficulty chewing (OR 2.41, 95% CI 1.52-3.83), dry mouth (OR 1.68, 95% CI 1.07-2.64), body pain (OR 1.78, 95% CI 1.14-2.78), Japan Science and Technology Agency Index of Competence scores (OR 0.91, 95% CI 0.84-0.99), physical activities (OR 0.99, 95% CI 0.98-1.00), Geriatric Depression Scale-15 scores (OR 1.13, 95% CI 1.05-1.21) and organization activities (OR 1.94, 95% CI 1.22-3.07). Covariance structural analyses showed that both "difficulty chewing" and "dry mouth" significantly affected "decrease in frequency of going out." In addition, decrease in frequency of going out was significantly affected by " Geriatric Depression Scale-15 scores" through oral function. Conclusions The relationship between oral function and decrease in frequency of going out was clarified, after the multifaceted factors were adjusted. Geriatr Gerontol Int 2019; center dot center dot: center dot center dot-center dot center dot

Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity▿

Keap1 and Cul3 constitute a unique ubiquitin E3 ligase that degrades Nrf2, a key activator of cytoprotective genes. Upon exposure to oxidants/electrophiles, the enzymatic activity of this ligase complex is inhibited and the complex fails to degrade Nrf2, resulting in the transcriptional activation of Nrf2 target genes. Keap1 possesses several reactive cysteine residues that covalently bond with electrophiles in vitro. To clarify the functional significance of each Keap1 cysteine residue under physiological conditions, we established a transgenic complementation rescue model. The transgenic expression of mutant Keap1(C273A) and/or Keap1(C288A) protein in Keap1 null mice failed to reverse constitutive Nrf2 activation, indicating that cysteine residues at positions 273 and 288 are essential for Keap1 to repress Nrf2 activity in vivo. In contrast, Keap1(C151S) retained repressor activity and mice expressing this molecule were viable. Mouse embryonic fibroblasts from Keap1(C151S) transgenic mice displayed decreased expression of Nrf2 target genes both before and after an electrophilic challenge, suggesting that Cys151 is important in facilitating Nrf2 activation. These results demonstrate critical roles of the cysteine residues in vivo in maintaining Keap1 function, such that Nrf2 is repressed under quiescent conditions and active in response to oxidants/electrophiles

Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia

<div><p>Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.</p></div

Dot plots of the SRS-A total raw scores for the 7 subgroups.

<p>Bar indicates median score: solid line for unremitted subjects and broken line for remitted subjects. Solid dot indicates unremitted subjects and cross indicates remitted subjects. HC: healthy control. MDD: major depressive disorder. BPD: bipolar disorder. SZ: schizophrenia.</p

Comparison of the degree of ALTs among the 7 subgroups.

<p>SRS-A total scores were compared among the 7 subgroups (i.e., HC and remitted/unremitted MDD, BPD and SZ) using Kruskal Wallis test; Dunn's test was used for further pair-wise multiple comparison. Results of pair-wise comparison between each clinical subgroup and HC are shown with error bar showing quartile deviation. HC: healthy control. MDD: major depressive disorder. BPD: bipolar disorder. SZ: schizophrenia. R: remitted. U: unremitted. n.s. <i>p</i>>0.05, * <i>p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.001 (all against HC)</p