Action Potentials that Go the Distance

AbstractDendrodendritic inhibition between mitral and granule cells in the olfactory bulb is thought to play an important role in olfactory discrimination. In this issue of Neuron, Xiong and Chen (2002) explore the propagation of action potentials along the secondary dendrites of mitral cells and their modulation by dendrodendritic inhibition

Pharmacology of fragrance: odors and GPCRs

Odor receptors are the largest family of GPCR’s on the planet. The identification of this large family of genes by Buck and Axel in 1991 showed that they have much in common with the other 450 or so GPCRs found in the mammalian genome. From this one might imagine that they can be profitably studied by using techniques developed for standard GPCR pharmacology – ligand screening, structure activity relations, and a variety of modeling techniques. We have utilized synthetic chemistry to examine the structure-function activity of an odor receptor by utilizing a variety of synthetically designed ligands that demonstrate mechanisms for agonism, antagonism, partial agonism and reverse agonism. These analyses provide a theoretical picture of the requirements for a binding region within the receptor. The existence of a range of ligands – from antagonists to high affinity agonists - for a given receptor must be taken into account when considering the type of upstream brain circuits that might be required to reduce the complex diversity of odor stimuli to the simpler categories of fragrance perception. In addition to these common principles of pharmacology that can be applied profitably to odor receptors we suggest that the techniques and strategies of medicinal chemistry, normally targeted to a single specific receptor (e.g., dopamine, epinephrine, serotonin) can be modified for use in a large and varied receptor population. The med chem concept of bioisosterism, for example, may help to better define our thinking about broad and narrow tuning in receptors when applied to large numbers of receptors

Functional odor classification through a medicinal chemistry approach

Crucial for any hypothesis about odor coding is the classification and prediction of sensory qualities in chemical compounds. The relationship between perceptual quality and molecular structure has occupied olfactory scientists throughout the 20th century, but details of the mechanism remain elusive. Odor molecules are typically organic compounds of low molecular weight that may be aliphatic or aromatic, may be saturated or unsaturated, and may have diverse functional polar groups. However, many molecules conforming to these characteristics are odorless. One approach recently used to solve this problem was to apply machine learning strategies to a large set of odors and human classifiers in an attempt to find common and unique chemical features that would predict a chemical’s odor. We use an alternative method that relies more on the biological responses of olfactory sensory neurons and then applies the principles of medicinal chemistry, a technique widely used in drug discovery. We demonstrate the effectiveness of this strategy through a classification for esters, an important odorant for the creation of flavor in wine. Our findings indicate that computational approaches that do not account for biological responses will be plagued by both false positives and false negatives and fail to provide meaningful mechanistic data. However, the two approaches used in tandem could resolve many of the paradoxes in odor perception

Applying medicinal chemistry strategies to understand odorant discrimination

Associating an odorant’s chemical structure with its percept is a long-standing challenge. One hindrance may come from the adoption of the organic chemistry scheme of molecular description and classification. Chemists classify molecules according to characteristics that are useful in synthesis or isolation, but which may be of little importance to a biological sensory system. Accordingly, we look to medicinal chemistry, which emphasizes biological function over chemical form, in an attempt to discern which among the many molecular features are most important for odour discrimination. Here we use medicinal chemistry concepts to assemble a panel of molecules to test how heteroaromatic ring substitution of the benzene ring will change the odour percept of acetophenone. This work allows us to describe an extensive rule in odorant detection by mammalian olfactory receptors. Whereas organic chemistry would have predicted the ring size and composition to be key features, our work reveals that the topological polar surface area is the key feature for the discrimination of these odorants

Selective Gene Expression by Postnatal Electroporation during Olfactory Interneuron Neurogenesis

Neurogenesis persists in the olfactory system throughout life. The mechanisms of how new neurons are generated, how they integrate into circuits, and their role in coding remain mysteries. Here we report a technique that will greatly facilitate research into these questions. We found that electroporation can be used to robustly and selectively label progenitors in the Subventicular Zone. The approach was performed postnatally, without surgery, and with near 100% success rates. Labeling was found in all classes of interneurons in the olfactory bulb, persisted to adulthood and had no adverse effects. The broad utility of electroporation was demonstrated by encoding a calcium sensor and markers of intracellular organelles. The approach was found to be effective in wildtype and transgenic mice as well as rats. Given its versatility, robustness, and both time and cost effectiveness, this method offers a powerful new way to use genetic manipulation to understand adult neurogenesis