The hippocampus is a medial temporal lobe structure in the brain and is widely studied for its role in memory and learning, in particular, spacial memory and emotional responses. It was thought to be a homogenous structure but emerging evidence shows differentiation along the dorsoventral axis and even microdomains for functional and cellular markers. We have examined in two cell-types of the hippocampal projection neurons, the dentate gyrus (DG) granule cells and CA3 pyramidal neurons, if the GABA-activated tonic current density varied between the dorsal (septal) and the ventral (temporal) poles of the male mouse hippocampus. Tonic synaptic currents, arising from spontaneous and miniature inhibitory postsynaptic currents (sIPSC, mIPSC), and extrasynaptic tonic currents were evaluated. The results revealed different levels of sIPSC but not mIPSC density between the dorsal and ventral hippocampal neurons for both the DG granule cells and the CA3 pyramidal neurons. The extrasynaptic tonic current density was larger in the DG granule cells as compared to the CA3 pyramidal neurons but did not vary between the dorsal and ventral regions. IPSC bursting was observed in both cell-types in the ventral hippocampus but was more common in the CA3 pyramidal neurons. Only in the dorsal DG granule cells was the level of the sIPSC and mIPSC density similar. The results indicate that the tonic GABAergic inhibition is particularly strong in the ventral hippocampal DG granule cells and enhanced in the dorsal as compared to the ventral hippocampal CA3 pyramidal neurons.

Aim We examined if tonic γ‐aminobutyric acid (GABA)‐activated currents in primary hippocampal neurons were modulated by insulin in wild‐type and tg‐APPSwe mice, an Alzheimer's disease (AD) model. Methods GABA‐activated currents were recorded in dentate gyrus (DG) granule cells and CA3 pyramidal neurons in hippocampal brain slices, from 8 to 10 weeks old (young) wild‐type mice and in dorsal DG granule cells in adult, 5‐6 and 10‐12 (aged) months old wild‐type and tg‐APPSwe mice, in the absence or presence of insulin, by whole‐cell patch‐clamp electrophysiology. Results In young mice, insulin (1 nmol/L) enhanced the total spontaneous inhibitory postsynaptic current (sIPSCT) density in both dorsal and ventral DG granule cells. The extrasynaptic current density was only increased by insulin in dorsal CA3 pyramidal neurons. In absence of action potentials, insulin enhanced DG granule cells and dorsal CA3 pyramidal neurons miniature IPSC (mIPSC) frequency, consistent with insulin regulation of presynaptic GABA release. sIPSCT densities in DG granule cells were similar in wild‐type and tg‐APPSwe mice at 5‐6 months but significantly decreased in aged tg‐APPSwe mice where insulin normalized currents to wild‐type levels. The extrasynaptic current density was increased in tg‐APPSwe mice relative to wild‐type littermates but, only in aged tg‐APPSwe mice did insulin decrease and normalize the current. Conclusion Insulin effects on GABA signalling in hippocampal neurons are selective while multifaceted and context‐based. Not only is the response to insulin related to cell‐type, hippocampal axis‐location, age of animals and disease but also to the subtype of neuronal inhibition involved, synaptic or extrasynaptic GABAA receptors‐activated currents.

Introduction: Breast cancer is the most common cancer in women and the second most frequent cause of cancer death. Several factors affect response to chemotherapy including nodal status, hormonal status and human epidermal growth factor receptor (Her-2). Aim of Study: The study is aiming at evaluating Caspase-3, 7 levels in serum of patients with locally advanced and metastatic breast cancer and establishing the relation between Casepase level and response to chemotherapy. Patients and Methods: The study was performed at Al Bairouni University Hospital and the Faculty of Pharmacy (Damascus-Syria). We have included 60 patients with histologic confirmation of invasive ductal carcinoma of the breast treated with the combination (Docetaxel + Doxorubicin) with Caspase-3, 7 levels to be evaluated before treatment and 24 hours after the first and third cycle. Results: Caspase-3 level increases in serum 24 hours after the 1 st cycle correlated with different kinds of response in 39 patients (P value 0.0002) with better results in those with Estrogen Receptors (ER) positive patients (P 0.005). In a similar manner, Caspase-7 level increases 24 hours after the 1 st cycle correlated with response in 40 patients (P 0.005). However, ER status had no impact on response in Caspase-7 group (P 0.2). Conclusion: Caspase-3 and 7 levels in serum are useful as a predictive marker of response to chemotherapy in both locally advanced and metastatic breast cancer especially when tittered 24 hours after the first chemotherapy.

Metabolic programs of immune cells are closely linked to their effector functions, where physiological molecules provide environmental cues and guidance. Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels and glucose is the main source of energy and a precursor for many biomolecules in T cells, whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system. Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4+ T cells, when the glucose concentration was elevated above normal levels. In a glucose concentration-dependent manner, insulin enhanced the GABAA receptors activated currents and GABA-dependent Ca2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na+-glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4+ T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. This study exposes concerted effects of GABA, glucose and insulin on CD4+ T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4+ T cells function.