The San Diego Nathan Shock Center: tackling the heterogeneity of aging.

Understanding basic mechanisms of aging holds great promise for developing interventions that prevent or delay many age-related declines and diseases simultaneously to increase human healthspan. However, a major confounding factor in aging research is the heterogeneity of the aging process itself. At the organismal level, it is clear that chronological age does not always predict biological age or susceptibility to frailty or pathology.

The National Heart, Lung, and Blood Institute Small Business Program: A Comprehensive Ecosystem for Biomedical Product Development.

Small companies working to develop products in the cardiovascular space face numerous challenges, from regulatory, intellectual property, and reimbursement barriers to securing funds to keep the lights on and reach the next development milestone. Most small companies that spin out from universities have the scientific knowledge, but product development expertise and business acumen are also needed to be successful. Other challenges include reduced interest in early stage technologies (Pharma & Biotech 2015 in Review, EP Vantage) and limited deal flow for cardiovascular products (Gormley B.

Acute inactivation of PSD-95 destabilizes AMPA receptors at hippocampal synapses.

Postsynatptic density protein (PSD-95) is a 95 kDa scaffolding protein that assembles signaling complexes at synapses. Over-expression of PSD-95 in primary hippocampal neurons selectively increases synaptic localization of AMPA receptors; however, mice lacking PSD-95 display grossly normal glutamatergic transmission in hippocampus. To further study the scaffolding role of PSD-95 at excitatory synapses, we generated a recombinant PSD-95-4c containing a tetracysteine motif, which specifically binds a fluorescein derivative and allows for acute and permanent inactivation of PSD-95.

cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.

Neuronal differentiation is accomplished through cascades of intrinsic genetic factors initiated in neuronal progenitors by external gradients of morphogens. Activity has been thought to be important only late in development, but recent evidence suggests that activity also regulates early neuronal differentiation. Activity in post-mitotic neurons before synapse formation can regulate phenotypic specification, including neurotransmitter choice, but the mechanisms are not clear.

NF-kappaB, IkappaB, and IRAK control glutamate receptor density at the Drosophila NMJ.

NF-kappaB signaling has been implicated in neurodegenerative disease, epilepsy, and neuronal plasticity. However, the cellular and molecular activity of NF-kappaB signaling within the nervous system remains to be clearly defined. Here, we show that the NF-kappaB and IkappaB homologs Dorsal and Cactus surround postsynaptic glutamate receptor (GluR) clusters at the Drosophila NMJ.

Mechanisms underlying the rapid induction and sustained expression of synaptic homeostasis.

Homeostatic signaling systems are thought to interface with the mechanisms of neural plasticity to achieve stable yet flexible neural circuitry. However, the time course, molecular design, and implementation of homeostatic signaling remain poorly defined. Here we demonstrate that a homeostatic increase in presynaptic neurotransmitter release can be induced within minutes following postsynaptic glutamate receptor blockade.

Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo.

Neurotransmission requires a balance of synaptic vesicle exocytosis and endocytosis. Synaptotagmin I (Syt I) is widely regarded as the primary calcium sensor for synaptic vesicle exocytosis. Previous biochemical data suggest that Syt I may also function during synaptic vesicle endocytosis; however, ultrastructural analyses at synapses with impaired Syt I function have provided an indirect and conflicting view of the role of Syt I during synaptic vesicle endocytosis.

Controlling the active properties of excitable cells.

Molecular perturbations of neurons, including genetic knockout and transgenic approaches, have provided insight into the cellular processes underlying neuronal function and plasticity. A detailed understanding of how individual neurons participate in the circuitry that controls behavior, however, will require the ability to experimentally manipulate the active properties of neurons in vivo. Recent technologies have greatly advanced our experimental ability to modulate the active properties of neurons with spatial and temporal precision; technical advances have been applied to the investigation of a diverse array of neurobiological questions.

Transgenically encoded protein photoinactivation (FlAsH-FALI): acute inactivation of synaptotagmin I.

We demonstrate a noninvasive technique for protein photoinactivation using a transgenically encoded tag. A tetracysteine motif that binds the membrane-permeable fluorescein derivative 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein (FlAsH) was engineered into synaptotagmin I (Syt I4C). Neuronally expressed Syt I4C rescues the syt I null mutation, can be visualized after FlAsH labeling, and is normally distributed at the Drosophila neuromuscular synapse.