As Ntrk2 selleck chemicals is the post synaptic entry point to the BDNF Ntrk2 signalling cascade, reduced ntrk2 levels might be expected to affect each of these intracellular sig nalling cascades and have significant impact on diverse Inhibitors,Modulators,Libraries cell functions. Indeed, genetically reduced BDNF Ntrk2 levels result in altered activity dependent synaptogenesis, synaptic function, such as LTP, learning and, importantly, stress related behaviours. Our RT qPCR data indicate that sub chronic stress induced re duction in Ntrk2 transcript levels may in fact not impact each of these signalling pathways. For example, both the PI3K Akt and MAPK ERK pathways were affected by sub chronic stress, but the PLC 1 was spared.

One important downstream target of the PI3K Akt Inhibitors,Modulators,Libraries and MAPK ERK pathways is the mammalian target of rapamycin, a kinase involved in many cellular processes, including translation of synaptic proteins that underpin plasticity, and, therefore, potentially important in the development of the depressive state. Although mTOR was not identified as being differen tially expressed by microarray, using RT qPCR we found it to be significantly reduced, consistent with Inhibitors,Modulators,Libraries changes in the aforementioned upstream regulatory pathways. This is supportive for a potential role in maladaptive neuronal plasticity contributing to the depressive state, although this will obviously require further experimental elucida tion, particularly at the protein level. Interestingly, antidepressant treatment with fluoxetine only prevented the sub chronic stress induced changes in the PI3K Akt pathway related transcripts, with B RAF and MAPK1 gene tran scripts of the MAPK ERK pathway not significantly dif ferent to the stress without fluoxetine levels.

This may indicate that the effects of fluoxetine antidepressant treatment are preferentially mediated by the PI3K Akt Inhibitors,Modulators,Libraries pathway, at least in this brain region, and suggest that targeting components of this pathway may be of future therapeutic interest. In this regard it is notable that GSK3B has been implicated in the pathophysiology of mood disorders. For example, GSK3B is one target Inhibitors,Modulators,Libraries for the mood stabilising drug lithium, it is also required for the antidepressant effects of ketamine, and in MDD sufferers, GSK3B kinase activity is increased in the PFC. Consistent with a role for GSK3B in de pression, fluoxetine increases phosphorylation of GSK3B at a specific N terminal serine residue, thereby decreas ing the kinases activity.

together Conversely, increasing GSK3B activity through viral mediated overexpression, induces a depression like phenotype in an animal model. How a reduction in GSK3B at the transcript level, as seen in the present study, fits into this scheme is not clear. Interestingly though, and consistent with our data, GSK3B gene expression but not protein levels, was reduced in the nucleus accumbens of depression susceptible animals in a chronic social defeat model of depression.