This Week in The Journal

Olfactory Marker Protein Regulates Basal, Odorant-Induced Signaling

Michele Dibattista and Johannes Reisert

Olfactory neurons detect odors in the environment, each using just one specific odorant receptor (OR) among thousands. Following activation of ORs, intracellular signaling commences: activation of adenylyl cyclase III (AC3) raises levels of cAMP, which in turn opens excitatory cyclic nucleotide-gated ion channels, causing the neurons to fire action potentials that terminate in the olfactory bulb. During olfactory exploration, mice increase their breathing rate from 2 to 10 Hz, a rapid sampling rate that requires tight regulation of cAMP both at baseline and during odorant stimulation. Researchers have long wondered what molecules control cAMP to accommodate the fast signaling.

Compared to wild-type mOR-EG-expressing neurons (left), those lacking OMP (right) had smaller responses to high concentrations of eugenol and larger responses to low concentrations of eugenol. See Dibattista and Reisert for details.

Dibattista and Reisert turned to the enigmatic olfactory marker protein (OMP), identified decades ago but still poorly understood. Previous work showed that olfactory discrimination was compromised in mice lacking OMP, and neurons lacking OMP responded to odors more slowly and fired fewer action potentials. Here, the researchers engineered transgenic mice that lacked OMP specifically in neurons containing one of two ORs: M71, activated by acetophenone, or mOR-EG, which detects eugenol. Basal activity of each neuron differs according to OR subtype expressed: M71 neurons are constitutively active whereas neurons containing mOR-EG have a low level of noise at rest. Electrophysiological recordings using the suction pipette technique showed that, compared to wild-type mice, olfactory neurons lacking OMP responded more slowly to odorants and responses were slower to terminate. Surprisingly, OMP regulated signaling in an OR-dependent way: peak response current was affected by loss of OMP in mOR-EG, but not M71, neurons. Neurons lacking OMP were less likely to fire action potentials in response to short-duration stimuli, regardless of OR type expressed. The researchers conclude that OMP serves to help olfactory neurons rapidly integrate stimuli, giving them their ability to detect high-frequency or brief exposure to odorants. Experiments using the phosphodiesterase inhibitor IBMX, which boosts cAMP, showed that OMP regulates basal as well as odorant-induced cAMP levels—also in an OR-dependent manner. The report identifies OR-dependent OMP function, revealing an underappreciated importance of individual ORs in determining olfactory neuronal physiology. The findings have implications beyond the olfactory system, as OMP has recently been found in tissues including the bladder, heart, and thyroid, along with ORs and AC3, where it is thought to contribute to chemosensation.

Glutamatergic Neurons in the Medial Septum Regulate Theta

Jennifer Robinson, Frédéric Manseau, Guillaume Ducharme, Bénédicte Amilhon, Erika Vigneault, et al.

(see pages 3016–3023)

Hippocampal theta rhythms, activity oscillations of around 6–10 Hz seen in the mammalian brain (not to be confused with the unrelated cortical theta rhythms seen in humans), are critical to learning and memory. The medial septum and diagonal band of Broca (MS-DBB) contribute heavily to theta oscillations—a contribution assumed to come from the region's well described cholinergic and GABAergic neurons. However, about a quarter of MS-DBB cells belong to a newly discovered glutamatergic population that expresses the type 2 vesicular glutamate transporter (vGLUT2). The excitatory cells project to a small population of pyramidal neurons and interneurons in the hippocampus and provide local inputs to both cholinergic and GABAergic septal neurons.

Robinson et al. used an optogenetic strategy to investigate the role of glutamatergic MS-DBB neurons further. They injected the septum of transgenic Cre-vGLUT2 mice with a virus containing the excitatory opsin ChETA labeled with yellow fluorescent protein, selectively labeling vGLUT2-expressing neurons and rendering them light-sensitive. In an in vitro septohippocampal preparation, optical activation of vGLUT2 septal neurons resulted in postsynaptic responses in septal neurons that were mostly GABAergic, with fewer cholinergic neurons responding. A smaller population of vGLUT2 neurons projected to the hippocampus, but functional connections were rare and responses small. In awake, behaving mice, optical stimulation of septal vGLUT2 neurons robustly modulated the frequency and rhythmicity of theta oscillations, whereas no such effects were seen with optical stimulation of the fornix, through which septal vGLUT2 neurons pass en route to the hippocampus. In contrast, in a control experiment when all fornix neurons were transfected to express the opsin ChR2, optical stimulation strongly modulated theta oscillations. The authors conclude that MS-DBB glutamatergic neurons provide strong local excitatory inputs to predominantly GABAergic (but also cholinergic) septal neurons to influence theta oscillations, and deliver only sparse inputs to the hippocampus with little effect on theta. Thus, a potential role for the glutamatergic neurons in the basal forebrain complex has emerged in learning and memory.