Smoking Progression and Nicotine-Enhanced Reward Sensitivity Predicted by Resting-State Functional Connectivity in Salience and Executive Control Networks.

INTRODUCTION: The neural underpinnings underlying individual differences in nicotine-enhanced reward sensitivity and smoking progression are poorly understood. Thus, we investigated whether brain resting-state functional connectivity (rsFC) during smoking abstinence predicts nicotine-enhanced reward sensitivity and smoking progression in young light smokers. We hypothesized that high rsFC between brain areas with high densities of nicotinic receptors (insula, anterior cingulate cortex [ACC], hippocampus, thalamus) and areas involved in reward-seeking (nucleus accumbens [NAcc], prefrontal cortex [PFC]) would predict nicotine-enhanced reward sensitivity and smoking progression. METHODS: Young light smokers (N=64, age 18-24, M = 1.89 cigarettes/day) participated in the study. These individuals smoked between 5 to 35 cigarettes per week and lifetime use never exceeded 35 cigarettes per week. Their rsFC was assessed using functional magnetic resonance imaging after 14-hour nicotine-deprivation. Subjects also completed a probabilistic reward task after smoking a placebo on one day and a regular cigarette on another day. RESULTS: The probabilistic-reward-task assessed greater nicotine-enhanced reward sensitivity was associated with greater rsFC between the right anterior PFC and right NAcc, but with reduced rsFC between the ACC and left inferior prefrontal gyrus and the insula and ACC. Decreased rsFC within the salience network (ACC and insula) predicted increased smoking progression across 18 months and greater nicotine-enhanced reward sensitivity. CONCLUSIONS: These findings provide the first evidence that differences in rsFCs in young light smokers are associated with nicotine-enhanced reward sensitivity and smoking progression. IMPLICATIONS: Weaker rsFC within the salience network predicted greater nicotine-enhanced reward sensitivity and smoking progression. These findings suggest that salience network rsFC and drug-enhanced reward sensitivity may be useful tools and potential endophenotypes for reward sensitivity and drug-dependence research.

Applications of Carbon Dots for the Treatment of Alzheimer's Disease.

There are currently approximately 50 million victims of Alzheimer's disease (AD) worldwide. The exact cause of the disease is unknown at this time, but amyloid plaques and neurofibrillary tangles in the brain are hallmarks of the disease. Current drug treatments for AD may slow the progression of the disease and improve the quality of life of patients, but they are often only minimally effective and are not cures. A major obstacle to developing and delivering more effective drug therapies is the presence of the blood-brain barrier (BBB), which prevents many compounds with therapeutic potential from reaching the central nervous system. Nanotechnology may provide a solution to this problem. Among the medical nanomaterials currently being studied, carbon dots (CDs) have attracted widespread attention because of their ability to cross the BBB, non-toxicity, and potential for drug/gene delivery.

Symbol relations training improves cognitive functioning in students with neurodevelopmental disorders.

Students with neurodevelopmental disorders [Specific Learning Disorders (SLD), Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD)] often experience learning challenges due to underlying weaknesses in cognitive processes. As these are some of the most common conditions to impact functioning, the development of effective treatments is a priority for neuropsychologists. However, the task of designing effective cognitive interventions has proven one of the most difficult challenges for our field. The Arrowsmith Program uses a novel approach compared to other cognitive intervention programs. We hypothesized that intensive practice of one aspect of this program would lead to improved cognitive functions in students with neurodevelopmental disorders. Twenty-seven students with neurodevelopmental disorders (ages 9.4-18.4 years) were recruited from Arrowsmith schools. Cognitive baseline and post-intervention data were gathered using components of the Woodcock-Johnson IV Tests of Cognitive Abilities. The intervention consisted of 6 weeks of intensive practice of the Symbol Relations Task. W-scores were used in a paired sample t-test analysis to determine if cognitive skill improvement occurred. Significant improvements were found in several measures of neuropsychological assessment, in particular in the Cattell-Horn-Carroll broad abilities These results provide a foundation for further work examining the utility of this novel approach to cognitive intervention.

Altered hippocampal astroglial metabolism is associated with aging and preserved spatial learning and memory.

An age-related decrease in hippocampal metabolism correlates with cognitive decline. Hippocampus-dependent learning and memory requires glutamatergic neurotransmission supported by glutamate-glutamine (GLU-GLN) cycling between neurons and astrocytes. We examined whether GLU-GLN cycling in hippocampal subregions (dentate gyrus and CA1) in Fischer 344 rats was altered with age and cognitive status. Hippocampal slices from young adult, aged cognitively-unimpaired (AU) and aged cognitively-impaired (AI) rats were incubated in artificial cerebrospinal fluid (aCSF) containing 1-13C-glucose to assess neural metabolism. Incorporation of 13C-glucose into glutamate and glutamine, measured by mass spectroscopy/liquid chromatography tandem mass spectroscopy, did not significantly differ between groups. However, when 13C-acetate, a preferential astrocytic metabolite, was used, a significant increase in 13C-labeled glutamate was observed in slices from AU rats. Taken together, the data suggest that resting state neural metabolism and GLU-GLN cycling may be preserved during aging when sufficient extracellular glucose is available, but that enhanced astroglial metabolism can occur under resting state conditions. This may be an aging-related compensatory change to maintain hippocampus-dependent cognitive function.

APOE genotype influences P3b amplitude and response to smoking abstinence in young adults.

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.

Author Correction: High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics.

Mining the antibody repertoire of plasma cells and plasmablasts could enable the discovery of useful antibodies for therapeutic or research purposes1. We present a method for high-throughput, single-cell screening of IgG-secreting primary cells to characterize antibody binding to soluble and membrane-bound antigens. CelliGO is a droplet microfluidics system that combines high-throughput screening for IgG activity, using fluorescence-based in-droplet single-cell bioassays2, with sequencing of paired antibody V genes, using in-droplet single-cell barcoded reverse transcription. We analyzed IgG repertoire diversity, clonal expansion and somatic hypermutation in cells from mice immunized with a vaccine target, a multifunctional enzyme or a membrane-bound cancer target. Immunization with these antigens yielded 100-1,000 IgG sequences per mouse. We generated 77 recombinant antibodies from the identified sequences and found that 93% recognized the soluble antigen and 14% the membrane antigen. The platform also allowed recovery of ~450-900 IgG sequences from ~2,200 IgG-secreting activated human memory B cells, activated ex vivo, demonstrating its versatility.

Butein attenuates the cytotoxic effects of LPS-stimulated microglia on the SH-SY5Y neuronal cell line.

Neuroinflammation is involved in brain aging and neuronal cell death in neurodegenerative diseases such as Alzheimer's disease (AD). Butein has been suggested to have anti-inflammatory, anti-apoptotic, and anti-cancer effects. However, few studies have been done to evaluate whether butein exerts protective effects on neurons, and the potential mechanism for this effect has not been studied. Here, we examined the effect of butein on SH-SY5Y neuroblastoma cells grown with conditioned medium from BV2 microglia cells that had been activated by lipopolysaccharide (LPS) as a neuroinflammation model. We found butein pretreatment significantly increased SH-SY5Y cell viability in a dose-dependent manner by inhibiting the apoptosis normally induced by microglia-conditioned medium. SH-SY5Y cells treated with microglia-conditioned medium showed upregulated ERK signaling pathway-related mRNA expression and protein phosphorylation, which was dose-dependently reversed by butein. Immunocytochemistry and Western blot results showed that BV2-LPS conditioned medium-induced Nuclear factor kappaB (NF-κB) transactivational activity in SH-SY5Y cells, but this was attenuated by butein treatment of the BV2 cells prior to their exposure to LPS. Collectively, our results indicate that butein effectively mitigates inflammatory injury caused by LPS-conditioned medium from microglia, possibly due to reductions in the transactivational activity of NF-κB p65 and ERK signaling pathway activation, and provide evidence for a neuroprotective role of butein through blocking negative consequences of microglial activation.

Impaired memory and marble burying activity in deformed epidermal autoregulatory factor 1 (Deaf1) conditional knockout mice.

Deleterious mutations within the DNA binding domain of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. While whole animal deletion of Deaf1 in mice is lethal, mice with conditional disruption of the gene in neuronal precursor cells can display memory deficits and increased anxiety-like behavior. This study aimed to further characterize learning and memory alterations and assess changes in marble burying activity and hippocampal size in mice with conditional deletion of Deaf1. Mice lacking DEAF1 in the CNS (NKO) displayed reduced memory in both contextual fear conditioning and a 3-day massed trials Morris water maze paradigm. NKO mice had reduced marble burying activity in full cage marble burying tests. Using a half-cage marble test, NKO mice again buried fewer marbles and spent significantly more time on the side of the cage away from the marbles compared to control animals. The area of the dorsal hippocampus of NKO mice was decreased compared to control and animals with a single Deaf1 allele. These results continue to establish the importance of DEAF1 in cognitive behavior and provide new evidence that DEAF1 regulates hippocampal morphology.

Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice.

Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-ß plaques; Aß) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

The effect of 22.5 kHz low-frequency contact ultrasound debridement (LFCUD) on lower extremity wound healing for a vascular surgery population: A randomised controlled trial.

The aim of this study was to compare changes in wound size and appearance and health complication rates in patients with vasculopathy and lower-extremity wounds treated with or without low-frequency contact ultrasound debridement (LFCUD) This study was a randomised controlled trial. The study was conducted in a vascular surgery service, including outpatient wound clinic and inpatient ward, in a tertiary care academic centre. In total, 70 patients with vasculopathy and lower-extremity wounds of mixed aetiology were enrolled in the trial; 68 completed the study. Patients were randomised to receive LFCUD plus usual care (n = 33) or usual care (n = 37) at 4 weekly visits, and were followed thereafter for up to 12 wk. The main outcome measures included closed wounds, change in wound surface area (WSA), and wound appearance by the revised Photographic Wound Assessment Tool (revPWAT). After 4 weekly LFCUD treatments, patients in the LFCUD group had significantly better wound appearance (total revPWAT score) compared with the control group treated only with usual care (P = <0.05). LFCUD-treated wounds also had a significant reduction in WSA over 4 wk that was not found in the UC group. LFCUD treatment was also associated with a greater number of healed wounds, odds ratio 5.00 (95% CI 1.24-20.25), and fewer instances of wound deterioration. Weekly LFCUD applications to patients with significant vasculopathy resulted in superior healing outcomes when compared with current usual wound care practice.

Evidence for altered insulin receptor signaling in Alzheimer's disease.

Epidemiological data have shown that metabolic disease can increase the propensity for developing cognitive decline and dementia, particularly Alzheimer's disease (AD). While this interaction is not completely understood, clinical studies suggest that both hyper- and hypoinsulinemia are associated with an increased risk for developing AD. Indeed, insulin signaling is altered in post-mortem brain tissue from AD patients and treatments known to enhance insulin signaling can improve cognitive function. Further, clinical evidence has shown that AD patients and mouse models of AD often display alterations in peripheral metabolism. Since insulin is primarily derived from the periphery, it is likely that changes in peripheral insulin levels lead to alterations in central nervous system (CNS) insulin signaling and could contribute to cognitive decline and pathogenesis. Developing a better understanding of the relationship between alterations in peripheral metabolism and cognitive function might provide a foundation for the development of better treatment options for patients with AD. In this article we will begin to piece together the present data defining this relationship by briefly discussing insulin signaling in the periphery and CNS, its role in cognitive function, insulin's relationship to AD, peripheral metabolic alterations in mouse models of AD and how information from these models helps understand the mechanisms through which these changes potentially lead to impairments in insulin signaling in the CNS, and potential ways to target insulin signaling that could improve cognitive function in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Preservative solution that stabilizes erythrocyte morphology and leukocyte viability under ambient conditions.

The deterioration of whole blood ex vivo represents a logistical hurdle in clinical and research settings. Here, a cocktail preservative is described that stabilizes leukocyte viability and erythrocyte morphology in whole blood under ambient storage. Neutrophil biostabilization was explored using a sophisticated microfluidic assay to examine the effectiveness of caspase inhibition to stabilize purified neutrophils. Following 72 h ambient storage, neutrophils remained fully functional to migrate towards chemical cues and maintained their ability to undergo NETosis after stimulation. Furthermore, stored neutrophils exhibited improved CD45 biomarker retention and reduced apoptosis and mortality compared to untreated controls. To stabilize erythrocyte morphology, a preservative solution was formulated using Taguchi methods of experimental design, and combined with the caspase inhibitor to form a whole blood cocktail solution, CSWB. CSWB was evaluated in blood from healthy donors and from women with metastatic breast cancer stored under ambient conditions for 72 h. CSWB-treated samples showed a significant improvement in erythrocyte morphology compared to untreated controls. Leukocytes in CSWB-treated blood exhibited significantly higher viability and CD45 biomarker retention compared to untreated controls. This 72 h shelf life under ambient conditions represents an opportunity to transport isolates or simply ease experimental timelines where blood degradation is problematic.

eConsultations to Infectious Disease Specialists: Questions Asked and Impact on Primary Care Providers' Behavior.

BACKGROUND: Since 2010, the Champlain BASE (Building Access to Specialist Advice through eConsultation) has allowed primary care providers (PCPs) to submit clinical questions to specialists through a secure web service. The study objectives are to describe questions asked to Infectious Diseases specialists through eConsultation and assess impact on physician behaviors. METHODS: eConsults completed through the Champlain BASE service from April 15, 2013 to January 29, 2015 were characterized by the type of question asked and infectious disease content. Usage data and PCP responses to a closeout survey were analyzed to determine eConsult response time, change in referral plans, and change in planned course of action. RESULTS: Of the 224 infectious diseases eConsults, the most common question types were as follows: interpretation of a clinical test 18.0% (41), general management 16.5 % (37), and indications/goals of treating a particular condition 16.5% (37). The most frequently consulted infectious diseases were as follows: tuberculosis 14.3% (32), Lyme disease 14.3% (32), and parasitology 12.9% (29). Within 24 hours, 63% of cases responded to the questions, and 82% of cases took under 15 minutes to complete. In 32% of cases, a face-to-face referral was originally planned by the PCP but was no longer needed. In 8% of cases, the PCP referred the patient despite originally not planning to make a referral. In 55% of cases, the PCP either received new information or changed their course of action. CONCLUSIONS: An eConsult service provides PCPs with timely access to infectious disease specialists' advice that often results in a change in plans for a face-to-face referral.

A survey of senior medical students' attitudes and awareness toward teaching and participation in a formal clinical teaching elective: a Canadian perspective.

BACKGROUND: To prepare for careers in medicine, medical trainees must develop clinical teaching skills. It is unclear if Canadian medical students need or want to develop such skills. We sought to assess Canadian students' perceptions of clinical teaching, and their desire to pursue clinical teaching skills development via a clinical teaching elective (CTE) in their final year of medical school. METHODS: We designed a descriptive cross-sectional study of Canadian senior medical students, using an online survey to gauge teaching experience, career goals, perceived areas of confidence, and interest in a CTE. RESULTS: Students at 13 of 17 Canadian medical schools were invited to participate in the survey (4154 students). We collected 321 responses (7.8%). Most (75%) respondents expressed confidence in giving presentations, but fewer were confident providing bedside teaching (47%), teaching sensitive issues (42%), and presenting at journal clubs (42%). A total of 240 respondents (75%) expressed interest in participating in a CTE. The majority (61%) favored a two week elective, and preferred topics included bedside teaching (85%), teaching physical examination skills (71%), moderation of small group learning (63%), and mentorship in medicine (60%). CONCLUSION: Our study demonstrates that a large number of Canadian medical students are interested in teaching in a clinical setting, but lack confidence in skills specific to clinical teaching. Our respondents signaled interest in participating in an elective in clinical teaching, particularly if it is offered in a two-week format.

Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aß) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggests that both type 1 and type 2 diabetes are risk factors for AD-related dementia and several clinical studies have demonstrated that AD patients show alterations in peripheral glucose regulation characterized by insulin resistance (hyperinsulinemia) or hypoinsulinemia. Whether animal models of AD exhibit a pre-diabetic phenotype without additional dietary or experimental manipulation is unclear however, with contradictory data available. Further, most studies have not examined the time course of potential pre-diabetic changes relative to AD pathogenesis and cognitive decline. Thus, in this study we tested the hypothesis that a pre-diabetic phenotype (peripheral metabolic dysregulation) exists in the APP/PS1 transgenic model of AD under normal conditions and precedes AD-related pathology. Specifically, we examined glucose tolerance in male APP/PS1 mice on a C57BL/6J congenic background at 2, 4-6 and 8-9months of age by assessing fasting glucose levels, glucose tolerance, plasma insulin levels and insulin sensitivity as well as the development of pathological characteristics of AD and verified that our APP/PS1 mice develop cognitive impairment. Here we show that APP/PS1 mice, compared to wild-type controls, exhibit a significant impairment in glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT) and a trend for increased fasting plasma insulin concentrations as early as 2months of age, while extracellular Aß1-42 deposition occurs later and cognitive decline exists at 8-9months of age. Moreover, APP/PS1 mice did not respond as well to exogenous insulin as the wild-type controls during an intraperitoneal insulin tolerance test (ipITT). Taken together, these data reveal that male APP/PS1 mice on a C57BL/6J congenic background exhibit a pre-diabetic phenotype prior to the development of AD-like pathology and that this metabolic deficit persists when they exhibit neuropathology and cognitive decline. This raises the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis.

Experimentally induced diabetes worsens neuropathology, but not learning and memory, in middle aged 3xTg mice.

Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The cause of the disease is still unknown, but amyloid plaques and neurofibrillary tangles in the brain are thought to play a role. However, transgenic mouse models expressing these neuropathological features do not show severe or consistent cognitive impairments. There is accumulating evidence that diabetes increases the risk for developing AD. We tested the hypothesis that experimentally induced diabetes would exacerbate cognitive symptoms in a mouse model of AD. Diabetes was induced in 12-month old 3xTg mice using streptozotocin (STZ; 90mg/kg, i.p., on two successive days). Hyperglycemia was verified by sampling blood glucose levels. Three months after injection (at 15 months of age), the mice were behaviorally tested in the Morris water maze and contextual fear conditioning. Subsequently, the hippocampal region was examined using immunohistochemistry (6E10 antibody for amyloid) and immunoblotting (AT8 antibody for phosphorylated tau). No differences were found in learning or memory between the vehicle-treated control and STZ-treated groups. A significant increase in the number of amyloid-positive plaques was observed in the subiculum of STZ-treated mice; very few plaques were seen in other hippocampal regions in either group. No differences in AT8 load were observed. These results reinforce that amyloid plaques, per se, are not sufficient to cause memory impairments. Further, while diabetes can enhance this aspect of brain pathology, the combination of disrupted glucose metabolism and the transgenes is still not sufficient to cause the severe cognitive impairments associated with clinical AD.

Sex Differences in Long-Term Potentiation at Temporoammonic-CA1 Synapses: Potential Implications for Memory Consolidation.

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory.

The essential role of hippocampal alpha6 subunit-containing GABAA receptors in maternal separation stress-induced adolescent depressive behaviors.

Exposure to early stressful adverse life events such as maternal separation severely impacts the development of the nervous system. Using immunohistochemistry, quantitative PCR and Western blot approaches, we found that alpha6 subunit-containing GABAA receptors (Gabra6-containing GABAA Rs) were expressed on hippocampal interneurons of adolescent rats. Maternal separation stress (MS) from postnatal day 2 to15 significantly reduced Gabra6 expression and provoked depressive behaviors such as anhedonia. Furosemide, the selective antagonist of Gabra6-containing GABAARs, strongly increased peak amplitude of evoked IPSCs at CA3-CA1 synapses and the frequency of miniature IPSPs recorded from CA1 pyramidal cells in naive control animals, and this effect was occluded in MS animals. Knockdown of Gabra6 expression in hippocampus mimicked furosemide's effect and was sufficient to produce similar depressive symptoms that were observed in MS animals. These results indicate that the Gabra6-containing GABAA R is a key modulator of hippocampal synaptic transmission and likely plays a crucial role in the pathophysiology of maternal separation-induced depression.

Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.

Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.