Inhibition of MAPK/ERK signaling blocks hippocampal neurogenesis and impairs cognitive performance in prenatally infected neonatal rats

Abstract

Hippocampus endogenous neurogenesis has been postulated to play a favorable role in brain restoration after injury. However, the underlying molecular mechanisms have been insufficiently deciphered. Here we investigated the potential regulatory capacity of MAPK/ERK signaling on neurogenesis and the associated cognitive performance in prenatally infected neonatal rats. From our data, intrauterine infection could induce hippocampal neuronal apoptosis and promote endogenous repair by evoking neural stem cell proliferation and survival. We also found intrauterine infection could induce increased levels of p-ERK, p-CREB and BDNF, which might be responsible for the potential endogenous rescue system. Furthermore, inhibition of MAPK/ERK signaling could aggravate hippocampal neuronal apoptosis, decrease neurogenesis, and impair the offspring's cognitive performances and could also down-regulate the levels of p-ERK, p-CREB and BDNF. Our data strongly suggest that the activation of MAPK/ERK signaling may play a significant role in promoting survival of newly generated neural stem cells via an anti-apoptotic mechanism, which may be particularly important in endogenous neuroprotection associated with cognitive performance development in prenatally infected rats.

Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats

“…GSB-214 activated the PI3K/AKT pathway only, which is mainly associated with neuroprotection 10. GSB-106 activated the MAP-kinase pathway along with the PI3K/AKT pathway, with the former playing a pivotal role in the mechanisms of neurogenesis and neuroplasticity 11,12. Previously, we reported that the dimeric dipeptide mimetic of NGF loop 4, which selectively activates the PI3K/AKT pathway, reduced brain infarct volume by approximately 18% in a model of MCAO in rats 21.…”

“…The PI3K/AKT pathway has been associated mainly with neuroprotection 10. The MAPK pathway is also involved in neuroprotection and plays a pivotal role in the mechanisms of neurogenesis and neuroplasticity 11,12…”

“…Treatments with GSB-106 or GSB-214 caused significant reductions in brain infarct size and improvement of neurological outcomes, with GSB-106 demonstrating greater in vivo efficacy than GSB-214. The greater effects of GSB-106 could be explained by the fundamental role of the MAPK/ERK pathway in neurogenesis and neuroplasticity,11,12 which are key factors in post-stroke recovery. Hence, GSB-214, which activated only the PI3K/AKT pathway, showed less pharmacological activity in this model.…”

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

“…Neurogenesis which has been shown to be involved in cognitive impairment and depression in humans and in a variety of rodent models, is a function of serotonergic regulation and may affect the response to antidepressants in both cognitive and affective behavioral domains (Adeosun et al, 2014;Alenina and Klempin, 2015;Anacker, 2014;Biscaro et al, 2012;Braun and Jessberger, 2014;Chadwick et al, 2011;Cho et al, 2015;Dimitrov et al, 2014;Gundersen et al, 2013;Hill et al, 2015;Jiang et al, 2015;Lin and Wang, 2014;Mendez-David et al, 2013;Morais et al, 2014;O'Leary and Cryan, 2014;Parihar et al, 2013;Pereira Dias et al, 2014;Ransome et al, 2012;Rotheneichner et al, 2014;Schoenfeld and Cameron, 2015;Seib et al, 2013;Serafini et al, 2014;Shetty, 2014;Suarez-Pereira et al, 2015;Yau et al, 2014). In young adult mice, antidepressants increase stem cell proliferation (Hodes et al, 2010;Santarelli et al, 2003;Tanti et al, 2013).…”

Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia

“…Transcription factors by which the expression of growth factors is rigorously modulated receive great interest. CREB is a transcription factor that acts as a central regulator of NSPCs proliferation and survival, and common final phosphorylation substrate for several kinasemediated signaling pathways, including the cAMP/Protein kinase A pathway, calcium-calmodulin-m ediated NMDA receptor signaling, phosphatidylinositol 3-kinase (PI3K)/Akt pathway, as well as MAP kinase signaling (Peltier et al, 2007;Mantamadiotis et al, 2012;Faigle and Song, 2013;Jiang et al, 2015). Administration of pharmacological CREB activator (Nakagawa et al, 2002) or retroviral vector-mediated over-expression of wild-type CREB (Peltier et al, 2007) increases adult hippocampus neural progenitor proliferation, whereas dominant negative CREB (Peltier et al, 2007) or conditional gene knockout of CREB (Dworkin et al, 2009) exerts an opposed influence.…”