Targeting CNTF to increase adult forebrain neurogenesis

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DESCRIPTION (provided by applicant): Endogenous neural precursors in the adult brain might be useful in cell replacement therapies for neurological disorders. The development of treatments that would promote neurogenesis would be facilitated by identification of the endogenous regulators. We have shown that endogenous and injected ciliary neurotrophic factor (CNTF) promotes neurogenesis in the adult mouse subventricular zone in the adult mouse forebrain (SVZ). CNTF is produced mainly by astrocytes and Schwann cells, making it a potentially nervous system-selective drug target. We have shown that CNTF expression is regulated by dopaminergic innervation and through D2 dopamine receptors, which are present on GFAP+ SVZ cells and neural progenitors. We will determine which cells express which transmitter receptors, which cells produce CNTF and which ones respond directly to CNTF. The extent to which glial-derived CNTF mediates D2 receptor-induced neurogenesis will be tested by administering D2 agonist while CNTF is blocked. These experiments may identify a regulation mechanism of neurogenesis that is readily amenable to pharmacological intervention with orally active and clinically approved drugs, and does not rely on the presence of neurons that are lost in neurological disorders. The restricted neurogenesis and expression of CNTF in the SVZ and not the striatum may be determined by overlap between dopaminergic and serotonergic projections. Serotonin promotes neurogenesis through 5-HT1a receptors which are also found on SVZ astrocytes. We will determine whether a 5-HT1a receptor agonist also can increase CNTF expression and increases neurogenesis via CNTF. We will determine whether the D2 and 5-HT1a receptors together regulate this neurogenesis through CNTF. If so, it might be possible that a combination of low doses of 5-HT1a and D2 agonists would robustly stimulate neurogenesis in the SVZ, a strategy which ultimately would reduce side effects of regular doses. In addition, we are targeting receptors that would not increase the CNTF production in the peripheral nerves and rest of the body, which otherwise would result in systemic side effects. Finally, this idea will be tested in a focal stroke model, where neuron replacement in the neighboring neostriatum may be beneficial. This study may identify an important convergent neurogenesis-regulating mechanism that can selectively be manipulated with FDA-approved oral drugs.