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Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders., Author summary Neurons in the brain process and store information via the specialized structures called synapses. Excitatory synapses are located on the dendritic structures called dendritic spines. Despite its small size, each dendritic spine contains a highly complicated signaling network consisting of enormous number of proteins. It is believed that dysfunction of these proteins will affect synaptic transmission and causes cognitive deficits that underlie neurodevelopmental disorders such as intellectual disability (ID). Recently many novel ID-associated gene mutations have been identified. The next crucial step will be to delineate how the gene products function normally in the brain, which will lead to better understanding of the pathophysiology of ID. Human genetic studies have linked numerous mutations on TBC1D24, a gene whose function is not well-defined, to epilepsy and intellectual disability. Here we show that TBC1D24 is localized at excitatory synapses of neurons in the hippocampus, a brain region that is critical to learning and memory. By knocking down TBC1D24 expression through RNA interference or generation of transgenic mice harboring an ID-associated Tbc1d24 missense mutation that destabilizes the protein, we demonstrate that TBC1D24 deficiency impairs the maintenance of dendritic spines in the brain as well as memory formation. This study indicates that synaptic defects underlie the cognitive deficits of individuals carrying TBC1D24 gene mutations.

Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human-induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC-derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl-CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease-related synaptopathy.

Purpose: This study is to examine how viewing a Japanese garden affects Japanese patients with dementia. Background: In a previous study, authors explored the effect on individuals with Alzheimer’s disease of viewing an indoor Japanese garden at a nursing home in the United States and reported that viewing the garden significantly reduced the heart rate, evoked short-term and long-term memories, and improved behavioral symptoms. However, it was unclear whether these effects were caused by the design of Japanese garden or unfamiliarity of the design to Caucasians. Methods: We constructed a Japanese garden on the rooftop of a hospital in Japan and assessed with a total of 25 subjects on the following categories: (1) eye movement, (2) heart rate, and (3) behavior under four different conditions: (a) open view of the site before construction of the Japanese garden (the control space), (b) open view of the Japanese garden, (c) view of the Japanese garden through closed door, and (d) view of Japanese garden through closed door with the chrysanthemum scent. Findings/Results: Viewers’ eyes scanned larger area while viewing the Japanese garden, and viewing the Japanese garden significantly reduced heart rate and improved behavioral symptoms than the control space. We also found that the effect of viewing the same Japanese garden differed across three conditions: the view through an open door, a closed door, and a closed door with added scent.

Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of a Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia.

Background Inflammation plays a critical role in accelerating the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD) and ataxia telangiectasia (A-T). In A-T mouse models, LPS-induced neuroinflammation advances the degenerative changes found in cerebellar Purkinje neurons both in vivo and in vitro. In the current study, we ask whether ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), can have the opposite effect and delay the symptoms of the disease. Methods We tested the beneficial effects of ibuprofen in both in vitro and in vivo models. Conditioned medium from LPS stimulated primary microglia (LM) applied to cultures of dissociated cortical neurons leads to numerous degenerative changes. Pretreatment of the neurons with ibuprofen, however, blocked this damage. Systemic injection of LPS into either adult wild-type or adult Atm−/− mice produced an immune challenge that triggered profound behavioral, biochemical, and histological effects. We used a 2-week ibuprofen pretreatment regimen to investigate whether these LPS effects could be blocked. We also treated young presymptomatic Atm−/− mice to determine if ibuprofen could delay the appearance of symptoms. Results Adding ibuprofen directly to neuronal cultures significantly reduced LM-induced degeneration. Curiously, adding ibuprofen to the microglia cultures before the LPS challenge had little effect, thus implying a direct effect of the NSAID on the neuronal cultures. In vivo administration of ibuprofen to Atm−/− animals before a systemic LPS immune challenge suppressed cytological damage. The ibuprofen effects were widespread as microglial activation, p38 phosphorylation, DNA damage, and neuronal cell cycle reentry were all reduced. Unfortunately, ibuprofen only slightly improved the LPS-induced behavioral deficits. Yet, while the behavioral symptoms could not be reversed once they were established in adult Atm−/− animals, administration of ibuprofen to young mutant pups prevented their symptoms from appearing. Conclusion Inflammatory processes impact the normal progression of A-T implying that modulation of the immune system can have therapeutic benefit for both the behavioral and cellular symptoms of this neurodegenerative disease. Electronic supplementary material The online version of this article (10.1186/s12974-018-1338-7) contains supplementary material, which is available to authorized users.

Figure S2. (A-N). Ibuprofen pretreatment of THP-1 cells partially rescued LPS-induced neuronal damage. (A-H). Conditioned medium from ibuprofen pretreated THP-1 cells was harvested and applied to DIV14 cultured neurons. Ibuprofen has positive effect on neuronal survival and partially attenuated the appearance of CCEs as measured either by EdU or Ki67. n = 3 for each group. Two-way ANOVA was used for analyzing ibuprofen effect within each TM/LM treatment. (O). Oxidative stress in the cultured neuron was measured by 8-oxoguanine. LM from primary cultured microglia was then applied to neuronal culture. It significant increase the level of 8-oxoguanine while ibuprofen alleviate the oxidative stress in the culture system. Scale bar = 50 μm. n = 3 for each group (PDF 3439 kb)

Figure S4. Akt, MAPK and NFκB pathways were investigated in cerebellar lysates by immunoblotting (A, B). Ibuprofen failed to affect ERK, JNK, Akt or p65 phosphorylation during an LPS challenge (C, E, F, G and data not shown). It reduced p38 phosphorylation only in Atm+/+ cerebellum (D). n = 4 for each group. Two-way ANOVA was used for statistical analysis. *, p

Figure S1. Gene expression profile of microglia and THP-1 cells under LPS challenge and ibuprofen pretreatment. THP-1 cells were treated with ibuprofen (0, 3, 10, 40, 80, 200 μM) for 6 h and then challenged with LPS for 48 h. Gene expression of TNFα (D), ILIβ (E), IL6 (F), COX2 (G) and IL8 (H), SOCS3 (I), CD45 (J), CD11b (K), P50 (L) and P65 (M) was assessed by PCR. (A). Microglia were treated with LPS for 48 h and then assessed by qPCR. (B). qPCR analysis of microglia treated with LPS and ibuprofen. N = 3–4 for each group. Student’s unpaired t test was used to analyze the difference between vehicle and LPS treated groups. Two-way ANOVA was used for analyzing differences in LPS and ibuprofen treatments. *, p

Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.