Olfactory Training Prevents Olfactory Dysfunction Induced by Bulbar Excitotoxic Lesions: Role of Neurogenesis and Dopaminergic Interneurons

Abstract

Glutamatergic excitotoxicity is involved in pathologies affecting the central nervous system, including traumatic brain injury (TBI) and neurodegenerative diseases, such as Parkinson’s disease (PD), in which olfactory dysfunction is an early symptom. Interestingly, our group has recently shown that bilateral administration of the glutamate agonist, N-methyl-d-aspartate (NMDA) in the olfactory bulbs (OBs) induces an olfactory dysfunction 1 week after lesions. Although a wide range of treatments have been attempted, no standard therapy has been established to treat olfactory disorders. Increasing evidence suggests a beneficial effect of olfactory training (OT) in olfactory function. However, the mechanisms underlying OT effects remain unknown. We investigated the effects of OT on the olfactory dysfunction induced by excitotoxicity in bilateral OB NMDA–lesioned animals. We compared OT effects with the ones obtained with neuroprotective therapies (pramipexole and MK801). We studied the underlying mechanisms involved in OT effects investigating the changes in the subventricular zone (SVZ) neurogenesis and in the number of periglomerular dopaminergic interneurons. One week after lesion, NMDA decreased the number of correct trials in the olfactory discrimination tests in the non-trained group (p < 0.01). However, OT performed for 1 week after lesions prevented olfactory dysfunction (p < 0.01). Pramipexole did not prevent olfactory dysfunction, whereas MK801 treatment showed a partial recovery (p < 0.05). An increase in SVZ neurogenesis (p < 0.05) associated with an increase in OB dopaminergic interneurons (p < 0.05) was related to olfactory function prevention induced by OT. The present results suggest a role for dopaminergic OB interneurons underlying the beneficial effects of OT improving olfactory dysfunction in bilaterally OB NMDA–lesioned animals.

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This work was supported by a research grant (110610) from Fundació La Marató TV3.

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Correspondence to Concepció Marin or Joaquim Mullol.

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All experiments were carried out following the European (2010/63/UE) and Spanish (RD 53/2013) regulation for the care and use of laboratory animals and approved by the local Government (Generalitat de Catalunya). The Ethic’s Committee of our institution approved this study.

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Marin, C., Laxe, S., Langdon, C. et al. Olfactory Training Prevents Olfactory Dysfunction Induced by Bulbar Excitotoxic Lesions: Role of Neurogenesis and Dopaminergic Interneurons. Mol Neurobiol 56, 8063–8075 (2019). https://doi.org/10.1007/s12035-019-1639-6

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Keywords

  • Excitotoxicity
  • Olfaction
  • Olfactory training
  • Parkinson’s disease
  • Traumatic brain injury
  • Dopamine
  • Neurogenesis