Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway

Abstract

A key neurotrophin responsible for the survival and function of basal forebrain (BF) cholinergic neurons is brain-derived neurotrophic factor (BDNF). A number of studies now indicate that a source of this factor may be BF astrocytes. This study was designed to define the role of BF-astrocyte-derived BDNF on cholinergic neurons. Moreover, it investigated regulatory events that modulate BDNF content and release. In initial work BDNF derived from BF-astrocyte-conditioned medium (ACM) was found to increase both numbers of BF acetylcholinesterase (AChE+) cholinergic neurons and the cholinergic synthetic enzyme choline acetyltransferase (ChAT). Western blots, immunocytochemistry and pharmacological inhibition studies revealed that glutamate, through group I metabotropic glutamate receptors (mGluR), increases the intracellular levels of BDNF in BF astrocytes in culture, as well as its release. Furthermore, the release of BDNF is mediated by the actions of PLC, IP3 and internal stores of Ca2+. These results suggest that BF astrocytes serve as local sources of BDNF for cholinergic neurons, and that they may be regulated as such by the neuronal signal, glutamate, through the mediation of group I metabotropic receptors and the PLC pathway.

Mechanisms of BDNF regulation in asthmatic airway smooth muscle

“…Given that PLC activation by TrkB in neurons (23) and increased Ca 2ϩ release from the sarcoplasmic reticulum (SR) during airway inflammation have been reported (34,37), one could infer from our current data that increased PLC activity and IP3-induced SR Ca 2ϩ outflow following TNF-␣ treatment, may be due to the autocrine signaling by BDNF. Furthermore, our results in ASM cells are consistent with what is observed in neurons: PLC activation is a requisite for BDNF release (20).…”

“…Given its importance for synaptic regulation, several other pathways have been implicated for BDNF secretion in neurons, including PLC and PKC (8,20,29). These pathways are well recognized in ASM in the context of Ca 2ϩ regulation.…”

Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats

“…However, evidences from in vitro studies using cells cultured in conditions mimicking ischemia reveal that these factors are multiple. For instance, astrocytes express BDNF when dopamine, glutamate or cytokines are added to the culture medium (Jean et al, 2008;Miklic et al, 2004;Saha et al, 2006). Human cerebral endothelial cells produce substantial amount of BDNF when exposed to pro-inflammatory conditions and to reduced oxygen avaibility (Bayas et al, 2002;Wang et al, 2006), and microglial cells respond to media from damaged neurons by BDNF upregulation (Lai and Todd, 2008).…”

“…Because increased levels of BDNF mRNA were observed in degenerating and surviving neurons in the acute post-stroke period (Comelli et al, 1992;Kokaia et al, 1995;Rickhag et al, 2007;Zhao et al, 2000), it has been generally accepted that neurons are the predominant source of neosynthesized BDNF in the ischemic brain. However, the contribution of non neuronal cells is suspected from in vitro studies that report the ability of microglial cells, cerebral endothelial cells and astrocytes to express and secrete BDNF when exposed to conditions mimicking ischemia (Bayas et al, 2002;Jean et al, 2008;Lai and Todd, 2008;Miklic et al, 2004;Saha et al, 2006). In vivo, data reported BDNF expression by non neuronal cells such as astrocytes (Sato et al, 2009;Uchida et al 2010) or microglia (Batchelor et al, 1999;Madinier et al, 2009;Nagamoto-Combs et al, 2007) but, to the best of our knowledge, studies specifically designed to assess their exact contribution to BDNF production are lacking.…”

Effects of Positive Allosteric Modulators on Single-Cell Oscillatory Ca2+Signaling Initiated by the Type 5 Metabotropic Glutamate Receptor

“…These findings have required the study of Ca 2ϩ signaling behaviors using single-cell assays and suggest that at this level, PAMs and NAMs primarily mediate frequency rather than the amplitude modulation of the Ca 2ϩ signal. Alteration of the Ca 2ϩ oscillation frequency can have a number of (patho)physiological consequences, because changes in the frequency of Ca 2ϩ oscillations have previously been shown to influence the activation of specific Ca 2ϩ -dependent enzymes (De Koninck and Schulman, 1998), the synthesis and release of various gliotransmitters (Agulhon et al, 2008) and growth factors (Jean et al, 2008), and gene transcriptional activation patterns (Dolmetsch et al, 1998;Tomida et al, 2003). Therefore, the ability of mGlu5 receptor PAMs to alter the frequency of Ca 2ϩ oscillations in single cells has the potential to alter fundamentally the cell's interpreta- .…”