Abstract
Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.
Highlights
Today, we recognize that in the adult mammalian brain, a proliferating population of neural stem cells (NSCs) generate new neurons throughout the adulthood life via a mechanism known as adult neurogenesis [1, 2]
Previous studies have shown that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) or its specific receptor (PAC-1) exhibit behavioral abnormalities such as reduced anxiety-like behavior and abnormal social behavior as well as impairment of hippocampal long-term potentiation (LTP) [38,39,40,41,42]. These results indicate that PACAP signaling via PAC-1 has a critical role in the development and functional neural pathways that might play an important role in neuropsychiatric disorders [43], perhaps through the regulation of adult neurogenesis
The results show that 400 μM and 1 mM ketamine significantly impaired NSC viability in a dose-dependent manner (Fig 1)
Summary
We recognize that in the adult mammalian brain, a proliferating population of neural stem cells (NSCs) generate new neurons throughout the adulthood life via a mechanism known as adult neurogenesis [1, 2]. This process occurs in the subgranular zone (SGZ) of the hippocampus, which supplies new granule cells to the dentate gyrus (DG) of the hippocampus [3] and in the subventricular zone (SVZ) of the lateral ventricle, which provides cellular turnover in the olfactory bulb (OB) in the rodent brain [4] and in the striatum in the human brain [5]. The direct effect of ketamine on primary adult NSCs is unknown
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