Gain Control With A-Type Potassium Current: IA As A Switch Between Divisive And Subtractive Inhibition

Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron’s output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two “modes” of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, if IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods (plane analysis and fast-slow dissection) to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can “self-regulate” the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract

Toxic interaction between Th2 cytokines and Staphylococcus aureus in atopic dermatitis

Patients with atopic dermatitis (AD) are commonly colonized/infected with Staphylococcus aureus, and this bacterium is known to worsen the dermatitis. In this issue, Brauweiler et al. demonstrate a newly discovered mechanism by which Th2 cytokines involved in AD augments the toxicity of the lytic staphylococcal protein alpha toxin. This review presents mechanisms by which Th2 cytokines may interact with S. aureus to the detriment of the dermatitis

Gain control with A-type potassium current: IA as a switch between divisive and subtractive inhibition

Neurons process information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron's output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two "modes" of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. We use simulations and mathematical analysis of a neuron model to find the specific conditions for which inhibitory inputs have subtractive or divisive effects. We identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly- inactivating outward current acts as a switch between subtractive and divisive inhibition. If IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can "self-regulate" the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract.Comment: 20 pages, 11 figure

Triamcinolone with Vitamin D Synergistic Efficacy in Psoriasis

Psoriasis is one of the most common skin conditions in the United States affecting more than 8 million people. High amounts of vitamin D has been shown to be effective in treatment of psoriasis. It also has a well-documented safety profile at the doses and duration that will be used during this study. Triamcinolone and other topical corticosteroids are considered a first line treatment for mild to moderate psoriasis with a well-documented safety profile. Individually both of these medications have shown effectiveness in the management and treatment of mild to moderate psoriasis. This study is designed to test whether a combination therapy of topical 0.1% triamcinolone with 40,000 IU vitamin D3 daily is effective in treating mild to moderate psoriasis

UVB-Induced Microvesicle Particle Release in Human Skin in vivo is Diminished Following Oral Vitamin C and E Antioxidant Administration

An important question in photobiology asks how Ultraviolet B (UVB, 290 – 320 nm) radiation, which mostly absorbs in the outer epidermis of skin, can generate a systemic response such as immunosuppression. Previous in vitro and ex vivo studies demonstrate UVB-dependent release of bioactive molecule-containing microvesicle particles (MVPs) from keratinocytes. Furthermore, MVP release is diminished upon antioxidant administration. The purpose of this study is to examine UVB-induced MVP release and antioxidant response in vivo. In this IRB-approved study, 8 male participants with Fitzpatrick type I or II skin were treated with 1000 J/m2 UVB irradiation to a 5 by 5 mm area of volar forearm skin. 4 hours later, punch biopsies and erythema measurements were performed. This procedure was repeated 8 days later following a course of oral antioxidants (vitamin C 2g/day, vitamin E 1000IU/day). On average, tissue MVP release increased 1.8-fold (+/- 0.31, P = 0.02) following UVB treatment. Following a course of oral antioxidants, the average UVB-induced tissue MVP release did not differ from the control (0.9-fold +/- 0.13, P = 0.23). There was no significant change in UVB-induced erythema between pre- and post-antioxidant administration. These studies suggest that UVB-MVP are dependent upon reactive oxygen species

Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms

Platelet-activating factor (PAF) stimulates numerous cell types via activation of the G protein-coupled PAF receptor (PAFR). PAFR activation not only induces acute proinflammatory responses, but it also induces delayed systemic immunosuppressive effects by modulating host immunity. Although enzymatic synthesis and degradation of PAF are tightly regulated, oxidative stressors, such as UVB, chemotherapy, and cigarette smoke, can generate PAF and PAF-like molecules in an unregulated fashion via the oxidation of membrane phospholipids. Recent studies have demonstrated the relevance of the mast cell (MC) PAFR in PAFR-induced systemic immunosuppression. The current study was designed to determine the exact mechanisms and mediators involved in MC PAFR-mediated systemic immunosuppression. By using a contact hypersensitivity model, the MC PAFR was not only found to be necessary, but also sufficient to mediate the immunosuppressive effects of systemic PAF. Furthermore, activation of the MC PAFR induces MC-derived histamine and PGE2 release. Importantly, PAFR-mediated systemic immunosuppression was defective in mice that lacked MCs, or in MC-deficient mice transplanted with histidine decarboxylase- or cyclooxygenase-2-deficient MCs. Lastly, it was found that PGs could modulate MC migration to draining lymph nodes. These results support the hypothesis that MC PAFR activation promotes the immunosuppressive effects of PAF in part through histamine- and PGE2-dependent mechanisms

How Wounding via Lasers Has Potential Photocarcinogenic Preventative Effects via Dermal Remodeling

As the incidence of non-melanoma skin cancer (NMSC) is increasing, there is a growing need to identify effective preventive strategies. A recently proposed hypothesis states that NMSC photocarcinogenesis is tightly linked to insufficient insulin growth factor-1 expression by agglomerated senescent fibroblasts in geriatric dermis. This paucity of IGF-1 expression in senile skin allows basal keratinocytes to mitotically propagate their UVB-altered genome and potentially initiate an actinic neoplasm. Here we review the role of the dermal microenvironment in NMSC pathogenesis, describe the impact of fibroblast senescence on this process and discuss how laser-induced dermal wounding can be effectively used to prevent NMSC development in geriatric patients

The IUPUI Signature Center for Atopic Dermatitis

poster abstractAtopic dermatitis is a chronic inflammatory skin disease characterized by dry skin, hypersensitivity to irritants and allergens, and significant pruritus. Atopic dermatitis is commonly associated with other atopic diseases including asthma, allergic rhinitis, and gastrointestinal disorders including eosinophilic esophagitis. Though a very common disease, there exists much misinformation and controversy/conflict in both the lay and medical communities about its pathogenesis and treatment, resulting in suboptimal care for the atopic dermatitis patient. Thus, education of both clinicians and lay public is needed. Inasmuch as atopic dermatitis is considered a systemic disorder, the optimal management should entail a multidisciplinary approach. Finally, research into the mechanisms by which atopic dermatitis occurs is needed to improve treatment of this common and quite debilitating disorder. The objective of the IUPUI Signature Center for Atopic Dermatitis is to provide optimal patient care, education and research in atopic dermatitis for the citizens of the state of Indiana. The Atopic Dermatitis has three separate components. First, we have developed an Atopic Dermatitis Working Group (ADWG) consisting of clinicians and scientists who meet on a monthly basis to disseminate information about research ideas/trials, and discuss topics and present difficult patients. Second, we have developed a monthly multidisciplinary AD clinic which has attracted the most challenging AD patients. Finally, we have developed infrastructure to assist in clinical and basic science research projects involving AD. Altogether, the IUPUI Signature Center for AD has been very successful as measured by the numbers of clinicians, researchers and patients who have been impacted by its presence

Platelet-Activating Factor-Receptor and Tumor Immunity

First described in 1972 by Benveniste and colleagues, platelet-activating factor (PAF) remains one of the potent phospholipid known to date. The role of PAF produced enzymatically in mediating diverse biological and pathophysiological processes including inflammatory and allergic diseases and cancers in response to various stimuli has been extensively studied. However, little is known about the role of non-enzymatically-generated PAF-like lipids produced in response to pro-oxidative stressors, particularly in modulating the host immune responses to tumor immunity, which is the focus of this review