Research reportType 4 phosphodiesterase inhibition impairs detection of low odor concentrations in mice
Introduction
Olfactory transduction begins when an odorant molecule binds to receptor sites on the cilia of receptor neurons. Odorant-receptor binding activates adenylyl cyclase through a second messenger cascade involving the G protein Golf, causing an increase in the level of adenosine 3′,5′-cyclic monophosphate (cAMP) [22]. Elevated levels of cAMP cause cyclic nucleotide gated channels to open, resulting in calcium influx and depolarization of the neuron [10], [18]. Cyclic nucleotide removal is mediated by phosphodiesterases (PDEs), which consist of a large 11-family group of enzymes found in virtually all tissues [9]. The predominant PDEs that occur in the rodent olfactory epithelium are members of the calcium-dependent PDE1 and cAMP-specific PDE4 families [3], [5], [28]. Within olfactory receptor neurons, these enzymes are subcellularly segregated: whereas PDE1 is found in the cilia, a PDE4 isoform (PDE4A) occurs in the cell bodies, axons and dendrites but is absent from the cilia [3], [4], [12].
The specific role of non-ciliary cAMP in general, and PDE4A in particular, in olfactory function is unclear. One possibility is that non-ciliary cAMP may modulate sensory perception. In one study, adrenaline or cAMP analogues applied to isolated, deciliated newt olfactory receptor cells in vitro suppressed spike generation in response to weak stimuli, yet increased spike frequency in response to moderate to strong stimuli [13]. The steepened slope of the intensity-response curve reflected cAMP-induced changes in contrast sensitivity, leading to the conclusion that cAMP localized outside of the olfactory sensory neuron cilia could contribute to certain aspects of olfactory perception [8], [13].
We sought to evaluate the potential involvement of PDE4A in odorant contrast by measuring olfactory discrimination in mice treated with rolipram, which is a specific inhibitor of mammalian PDE4s [23]. We asked whether increasing cAMP levels beyond the cilia by inhibition of PDE4A with rolipram could produce a behavioral manifestation of the stimulus–response properties seen by Kawai et al. [13] in olfactory neurons. Specifically, we examined whether rolipram treatment would decrease olfactory sensitivity of mice to increased dilutions of an odorant, yet enhance sensitivity at moderate to low dilutions. To investigate this question, mice were tested in two separate, appetitively motivated behavioral paradigms. In the first, an automated liquid dilution olfactometer was developed to measure the ability of water-deprived mice to: (a) distinguish a pure odorant from an odor mixture and (b) to detect increasing dilutions of a single odorant. In the second, food-deprived mice were tested in a food-motivated, two-choice discrimination task using cups of sand that were unscented or scented with different dilutions of an odorant.
Section snippets
Subjects
Adult male Swiss Webster mice (between 7 and 10 weeks of age at the beginning of testing) were obtained from Taconic Farms (Germantown, NY) and group-housed on a 12-h light:12-h dark cycle. On the two-choice discrimination task using scented sand, subjects (n = 9) were fed sufficient rodent chow daily to maintain 80–90% pre-testing ad libitum body weight, with feeding always following testing on test days. Water was continuously available. For olfactometer testing, a different set of subjects (n =
Odor mixtures
Mice treated with rolipram or vehicle readily distinguished AA-only from AA mixed with any of the three lowest dilutions of CIT (Fig. 2). However, performance began to decline under both rolipram and vehicle treatment once the dilution of CIT in the S− was brought to 0.01%, as indicated by two animals that failed to pass criterion on both the rolipram and vehicle tests. At the highest CIT dilution tested, all animals failed on both treatment conditions. Repeated measures ANOVA corroborated
Discussion
Electrophysiological observations on cAMP-induced spiking in newt olfactory sensory neurons led us to examine whether treatment of mice with the PDE4 inhibitor rolipram could increase the contrast between high and low odor concentrations. Kawai et al. [13] found that adrenaline could reversibly suppress responses of deciliated cells in vitro under weakly stimulated conditions, and strengthen responses to moderate and higher levels of input. These responses were mimicked by application of the
Acknowledgements
Supported by MH59200. We thank Dr. Michael Baum for a critical reading of an earlier version of the paper. We also appreciate the generous assistance of Dr. Howard Eichenbaum and members of his laboratory for helping us set up and establish the olfactory testing protocols.
References (28)
- et al.
Odour mixture suppression: evidence for a peripheral mechanism in human and rat
Brain Res
(1987) - et al.
Profoundly different calcium permeation and blockage determine the specific function of distinct cyclic nucleotide-gated channels
Neuron
(1995) - et al.
Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents
Eur J Pharmacol
(1997) - et al.
Mucosal activity patterns as a basis for olfactory discrimination: comparing behavior and optical recordings.
Brain Res
(2003) - et al.
Crossmodal associative memory representations in rodent orbitofrontal cortex
Neuron
(1999) - et al.
Presynaptic cyclic nucleotide-gated ion channels modulate neurotransmission in the mammalian olfactory bulb
Neuron
(2003) - et al.
Interactive effects of testosterone and superior cervical ganglionectomy on attraction thresholds to volatile urinary odors in gonadectomized mice
Behav Brain Res
(2003) - et al.
Rolipram: a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory.
Proc Natl Acad Sci USA
(1998) - et al.
Calcium/calmodulin-activated phosphodiesterase expressed in olfactory receptor neurons
J Neurosci
(1992) - et al.
A mouse homolog of dunce, a gene important for learning and memory in Drosophila, is preferentially expressed in olfactory receptor neurons
J Neurobiol
(1995)
Characterization of cAMP degradation by phosphodiesterases in the accessory olfactory system
Chem Senses
Behavioral models of odor similarity
Behav Neurosci
Physostigmine enhances performance on an odor mixture discrimination test
Physiol Behav
The smell of adrenaline
Nat Neurosci
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