Olfactory receptor neuron dysfunction in schizophrenia.

Olfactory impairments are a common feature of schizophrenia. Impairments in odor detection and odor identification are present early in the course of illness and among those at risk for the disorder. These behavioral impairments have been linked to both physiological and anatomical abnormalities in the neural substrates subserving olfaction, including relatively peripheral elements of the olfactory system. The location of olfactory receptor neurons in the nasal epithelium allows noninvasive access to these neurons in living subjects. This offers a unique opportunity to directly assess neuronal integrity in vivo in patients. The peripheral olfactory receptor neuron response to odor stimulation was assessed in 21 schizophrenia patients and 18 healthy comparison subjects. The electroolfactogram, representing the electrical depolarization of the olfactory receptor neurons, was recording following stimulation with different doses and durations of hydrogen sulfide, a pure olfactory nerve stimulant. Schizophrenia patients had abnormally large depolarization responses following odor stimulation, independent of clinical symptomatology, antipsychotic medication dosage or smoking history. Although the precise pathophysiological mechanism is unknown, this olfactory receptor neuron abnormality is consistent with several lines of evidence suggesting altered proliferation or maturation of olfactory receptor neuron cell lineages in schizophrenia. It is also consistent with emerging evidence of disruptions of cyclic AMP-mediated intracellular signaling mechanisms, and may be a marker of these disruptions. It unambiguously demonstrates that neurophysiological disturbances in schizophrenia are not limited to cortical and subcortical structures, but rather include even the most peripheral sensory neurons.

Olfactory epithelia exhibit progressive functional and morphological defects in CF mice.

In normal nasal epithelium, the olfactory receptor neurons (ORNs) are continuously replaced through the differentiation of progenitor cells. The olfactory epithelium (OE) of the cystic fibrosis (CF) mouse appears normal at birth, yet by 6 mo of age, a marked dysmorphology of sustentacular cells and a dramatic reduction in olfactory receptor neurons are evident. Electroolfactograms revealed that the odor-evoked response in 30-day-old CF mice was reduced approximately 45%; in older CF mice, a approximately 70% reduction was observed compared with the wild type (WT) response. Consistent with studies of CF airway epithelia, Ussing chamber studies of OE isolated from CF mice showed a lack of forskolin-stimulated Cl(-) secretion and an approximately 12-fold increase in amiloride-sensitive sodium absorption compared with WT mice. We hypothesize that the marked hyperabsorption of Na(+), most likely by olfactory sustentacular cells, leads to desiccation of the surface layer in which the sensory cilia reside, followed by degeneration of the ORNs. The CF mouse thus provides a novel model to examine the mechanisms of disease-associated loss of olfactory function.

Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis.

Olfactory receptor neurons (ORNs) were infected upon intranasal inoculation with the R404BP strain of neurovirulent influenza A virus. Virus-infected neurons and a small fraction of neighbouring uninfected neurons displayed apoptotic neurodegeneration substantiated by the immunohistochemistry for activated caspase-3 molecules and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling method. However, virus infection was restricted within the peripheral neuroepithelium and all mice survived the infection. Virus-infected ORNs revealed upregulated expression of the Fas ligand molecules, activating the c-Jun N-terminal kinase signal transduction pathway. In addition, Iba1-expressing activated microglia/macrophages appeared to partake in phagocytic activities, eventually clearing apoptotic bodies. These results raise the possibility that induction of apoptosis in olfactory receptor neurons at an early stage of infection may provide protective effects against invasion of the neurovirulent virus from the peripheral to the CNS.