Intragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice

Spinal muscular atrophy is caused by reduced levels of SMN resulting from the loss of SMN1 and reliance on SMN2 for the production of SMN. Loss of SMN entirely is embryonic lethal in mammals. There are several SMN missense mutations found in humans. These alleles do not show partial function in the absence of wild-type SMN and cannot rescue a null Smn allele in mice. However, these human SMN missense allele transgenes can rescue a null Smn allele when SMN2 is present. We find that the N- and C-terminal regions constitute two independent domains of SMN that can be separated genetically and undergo intragenic complementation. These SMN protein heteromers restore snRNP assembly of Sm proteins onto snRNA and completely rescue both survival of Smn null mice and motor neuron electrophysiology demonstrating that the essential functional unit of SMN is the oligomer.

Glucose-sensing mediated by portal GLP-1 receptor is markedly impaired in insulin-resistant obese animals

The glucose portal sensor informs the brain of changes in glucose inflow via vagal afferents that require an activated GLP-1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1-dependent portal glucose signaling was identified, in vivo, using a novel ⁶⁸Ga labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that, in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r-dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin-resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose.

Glucose-sensing mediated by portal GLP-1 receptor is markedly impaired in insulin-resistant obese animals

The glucose portal sensor informs the brain of changes in glucose inflow via vagal afferents that require an activated GLP-1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1-dependent portal glucose signaling was identified, in vivo, using a novel ⁶⁸Ga labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that, in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r-dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin-resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose.

Protonic conductor: better understanding neural resting and action potential

The newly formulated action potential equation provides biophysical insights for neuron electrophysiology, which may represent a complementary development to the classic Goldman–Hodgkin–Katz equation. The nonlinear curve of the localized protons/cations charge density in the real-time domain of an action potential spike appears as an inverse mirror image to the action potential. The biological significance of axon myelination is now elucidated as to provide protonic insulation and prevent any ions from interfering with action potential signal.

Evidence of structural and functional plasticity occurring within the intracardiac nervous system of spontaneously hypertensive rats

We have developed intracardiac neuron whole cell recording techniques in atrial preparations from control and spontaneous hypertensive rats. This has enabled the identification of significant synaptic plasticity in the intracardiac nervous system, including enhanced postsynaptic current frequency, increased synaptic terminal density, and altered postsynaptic receptors. This increased synaptic drive together with altered cardiac neuron electrophysiology could increase intracardiac nervous system excitability and contribute to the substrate for atrial arrhythmia in hypertensive heart disease.

Differential and synergistic roles of 17β-estradiol and progesterone in modulating adult female rat nucleus accumbens core medium spiny neuron electrophysiology

This research indicates that estradiol and progesterone act both differentially and synergistically to modulate neuron physiology in the nucleus accumbens core. These actions by specific hormones provide key data indicating the endocrine mechanisms underlying how the estrous cycle modulates neuron physiology in this region. Overall, these data reinforce that hormones are an important influence on neural physiology.