Formation of new neurons and their integration into existing neural networks is necessary for repair and change in the brain. Producing a larger supply of neurons could be beneficial, helping to resist the consequences of age-related damage that builds up over time. Here, researchers find a way to influence one source of new neurons using a diterpenoid compound that can be delivered intranasally to find its way into the brain. They demonstrate increased production of neurons in mice using this approach.
Neural stem cells from the subventricular zone (SVZ) neurogenic niche provide neurons that integrate in the olfactory bulb circuitry. However, in response to cortical injuries, the neurogenic activity of the SVZ is significantly altered, leading to increased number of neuroblasts with a modified migration pattern that leads cells towards the site of injury. Despite the increased neurogenesis and migration, many newly generated neurons fail to survive or functionally integrate into the cortical circuitry. Providing the injured area with the adequate signaling molecules may improve both migration and functional integration of newly generated neurons.
Protein kinases (PK) such as PKA or PKC have an important role in neuroblast migration. Previous reports have revealed that the treatment of mouse cortical injuries with a novel PKC activating diterpenoid resulted in neuroblast enrichment and in their differentiation into mature neurons. Within the injury environment and the SVZ, growth factors that promote proliferation and glial differentiation are highly expressed such as transforming growth factor alpha (TGFα) and they need to be counterbalanced with signals that promote differentiation such as neuregulins to allow regeneration and replacement of the lost neurons. Interestingly, evidence shows that in response to diterpenoid EOF2, which activates novel PKC activity and neuregulin release, these signaling cues may be altered to promote the premature differentiation of neuroblasts and their migration toward the injured area suggesting a role for neuregulin 1 (NRG1) and novel PKC in neuronal replacement in cortical injuries.
We have found that EOF2 treatment of adult mice with mechanical cortical injuries facilitates the delivery of neuroblasts into these injuries. The newly generated neurons develop features of fully functional neurons. Our results show that the newly generated neurons receive electrical inputs, fire action potentials, and undergo complete differentiation into neurons recapitulating the stages that distinguish ontogenic differentiation. These neurons develop features representative of neurons belonging the cortical layer in which they are situated. We have also studied that EOF2 facilitates neuregulin release in SVZ cells, a signaling factor that promotes neuronal differentiation. Neuregulin is expressed in microglial cells that reach the injury in response to the damage and its release is increased by EOF2 treatment.
Link: https://doi.org/10.1186/s13287-024-04105-4
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