Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development.

Shank3 is a structural protein found predominantly at the postsynaptic density. Mutations in the SHANK3 gene have been associated with risk for autism spectrum disorder (ASD). We generated induced pluripotent stem cells (iPSCs) from control individuals and from human donors with ASD carrying microdeletions of SHANK3. In addition, we used Zinc finger nucleases to generate isogenic SHANK3 knockout human embryonic stem (ES) cell lines. We differentiated pluripotent cells into either cortical or olfactory placodal neurons. We show that patient-derived placodal neurons make fewer synapses than control cells. Moreover, patient-derived cells display a developmental phenotype: young postmitotic neurons have smaller cell bodies, more extensively branched neurites, and reduced motility compared with controls. These phenotypes were mimicked by SHANK3-edited ES cells and rescued by transduction with a Shank3 expression construct. This developmental phenotype is not observed in the same iPSC lines differentiated into cortical neurons. Therefore, we suggest that SHANK3 has a critical role in neuronal morphogenesis in placodal neurons and that early defects are associated with ASD-associated mutations.

Understanding the role of steroids in typical and atypical brain development: Advantages of using a "brain in a dish" approach.

Steroids have an important role in growth, development, sexual differentiation and reproduction. All four classes of steroids, androgens, oestrogens, progestogens and glucocorticoids, have varying effects on the brain. Androgens and oestrogens are involved in the sexual differentiation of the brain, and also influence cognition. Progestogens such as progesterone and its metabolites have been shown to be involved in neuroprotection, although their protective effects are timing-dependent. Glucocorticoids are linked with stress and memory performance, also in a dose- and time-dependent manner. Importantly, dysfunction in steroid function has been implicated in the pathogenesis of disease. Moreover, regulating steroid-signalling has been suggested as potential therapeutic avenue for the treatment of a number of neurodevelopmental, psychiatric and neurodegenerative disorders. Therefore, clarifying the role of steroids in typical and atypical brain function is essential for understanding typical brain functions, as well as determining their potential use for pharmacological intervention in the atypical brain. However, the majority of studies have thus far have been conducted using animal models, with limited work using native human tissue or cells. Here, we review the effect of steroids in the typical and atypical brain, focusing on the cellular, molecular functions of these molecules determined from animal models, and the therapeutic potential as highlighted by human studies. We further discuss the promise of human-induced pluripotent stem cells, including advantages of using three-dimensional neuronal cultures (organoids) in high-throughput screens, in accelerating our understanding of the role of steroids in the typical brain, and also with respect to their therapeutic value in the understanding and treatment of the atypical brain.

Quantifying barcodes of dendritic spines using entropy-based metrics.

Spine motility analysis has become the mainstay for investigating synaptic plasticity but is limited in its versatility requiring complex, non automatized instrumentations. We describe an entropy-based method for determining the spatial distribution of dendritic spines that allows successful estimation of spine motility from still images. This method has the potential to extend the applicability of spine motility analysis to ex vivo preparations.

G-protein oestrogen receptor 1: trials and tribulations of a membrane oestrogen receptor.

Oestrogens are now recognised to be able to initiate rapid, fast responses, in addition to their classical, longer-term actions. There is a growing appreciation of the potential implications of this mode of action for oestrogenic signalling in both neuronal and non-neuronal systems. As such, much effort has been made to determine the mechanisms that are critical for transducing these rapid effects into cellular responses. Recently, an orphan G-protein-coupled receptor (GPCR), termed GPR30, was identified as an oestrogen-sensitive receptor in cancer cells. This receptor, now term G-protein oestrogen receptor 1 (GPER1) has been the subject of many investigations, and a role for this receptor in the nervous system is now emerging. In this review, we highlight some of the more recent advances in our understanding of the distribution and subcellular localisation of this receptor in the brain, as well as some of the evidence for the potential role that this receptor may play in the brain. We then discuss some of the controversies surrounding the pharmacology of this receptor, and attempt to reconcile these by suggesting that the 'agonist-specific coupling' model of GPCR function may provide a potential explanation for some of the divergent reports of GPER1 pharmacology.

Mechanisms underlying the interactions between rapid estrogenic and BDNF control of synaptic connectivity.

The effects of the steroid hormone 17ß-estradiol and the neurotrophin brain-derived neurotrophic factor (BDNF) on neuronal physiology have been well investigated. Numerous studies have demonstrated that each signal can exert powerful influences on the structure and function of synapses, and specifically on dendritic spines, both within short and long time frames. Moreover, it has been suggested that BDNF is required for the long-term, or genomic, actions of 17ß-estradiol on dendritic spines, via its ability to regulate the expression of neurotrophins. Here we focus on the acute, or rapid effects, of 17ß-estradiol and BDNF, and their ability to activate specific signalling cascades, resulting in alterations in dendritic spine morphology. We first review recent literature describing the mechanisms by which 17ß-estradiol activates these pathways, and the resulting alterations in dendritic spine number. We then describe the molecular mechanisms underlying acute modulation of dendritic spine morphology by BDNF. Finally, we consider how this new evidence may suggest that the temporal interactions of 17ß-estradiol and BDNF can occur more rapidly than previously reported. Building on these new data, we propose a novel model for the interactions of this steroid and neurotrophin, whereby rapid, non-genomic 17ß-estradiol and acute BDNF signal in a co-operative manner, resulting in dendritic spine formation and subsequent stabilization in support of synapse and circuit plasticity. This extended hypothesis suggests an additional mechanism by which these two signals may modulate dendritic spines in a time-specific manner.

Efficient Electrochemical Synthesis, Antimicrobial and Antiinflammatory Activity of 2-amino-5-substituted- 1,3,4-oxadiazole Derivatives.

An efficient electrochemical method for the preparation of 2-amino-5-substituted-1,3,4-oxadiazoles (4a-k) at platinum anode through the electrooxidation of semicarbazone (3a-k) at controlled potential electrolysis has been reported in the present study. The electrolysis was carried out in the acetic acid solvent and lithium perchlorate was used as supporting electrolyte. The products were characterized by IR,(1)H-NMR,(13)C-NMR, mass spectra and elemental analysis. The synthesized compounds were screened for their in vitro growth inhibiting activity against different strains of bacteria viz., Klebsilla penumoniae, Escherichia coli, Bassilus subtilis and Streptococcus aureus and antifungal activity against Aspergillus niger and Crysosporium pannical and results have been compared with the standard antibacterial streptomycin and antifungal griseofulvin. Compounds exhibits significant antibacterial activity and antifungal activity. Compounds 4a and g exhibited equal while 4c, d, i and j slightly less antibacterial activity than standard streptomycin. Compounds 4a and g exhibited equal while 4b, c, d, f and i displayed slightly less antifungal activity than standard griseofulvins.

SEXUALLY TRANSMITTED DISEASE: A CLINICAL PSYCHOLOGICAL PROFILE.

A clinical-psychological study of 400 consecutive patients with sexually transmitted disease (STD) was undertaken at 151 BH and MH Meerut during 1991-95. Majority of the STD patients were aged 34 years or less (90.25%), belonged to other ranks (68%), hailed from rural areas (90.75%), were Hindus (83.50%), were married (72.50%). Uncontrollable sexual urge was the reason for exposure in majority (69.25%) of the cases. Commonest source of STD was commercial sex workers (CSW) (72.80%). At the time of exposure 58.50% patients were at their place of work (on out-pass) and 11.75% had consumed alcohol. Commonest STDs were Chanchroid (30.50%), Syphilis (19.50%) and LGV (10.80%). A delay of more than one month from the onset of symptoms to reporting for treatment was observed in 18.50% patients, while 24.25% patients had taken treatment from unauthorised sources. A past history of STD was given by 8.80% of patients. Majority (57.75%) of the STD patients had inadequate knowledge of STD and only 6.75% had used a condom during exposure. Mean scores of STD patients on Maudsley personality inventory were: Neuroticism-37.98 and extroversion-46.03. The General Health questionnaire identified 19.75% patients as probable psychiatric cases. On clinical evaluation, psychiatric disorders were present in 5.75% of patients.