Modulation of Synaptic Transmission by the BCL-2 Family Protein BCL-xL

Abstract

BCL-2 family proteins are known to regulate cell death during development by influencing the permeability of mitochondrial membranes. The anti-apoptotic BCL-2 family protein BCL-xL is highly expressed in the adult brain and localizes to mitochondria in the presynaptic terminal of the adult squid stellate ganglion. Application of recombinant BCL-xL through a patch pipette to mitochondria inside the giant presynaptic terminal triggered multiconductance channel activity in mitochondrial membranes. Furthermore, injection of full-length BCL-xL protein into the presynaptic terminal enhanced postsynaptic responses and enhanced the rate of recovery from synaptic depression, whereas a recombinant pro-apoptotic cleavage product of BCL-xL attenuated postsynaptic responses. The effect of BCL-xL on synaptic responses persisted in the presence of a blocker of mitochondrial calcium uptake and was mimicked by injection of ATP into the terminal. These studies indicate that the permeability of outer mitochondrial membranes influences synaptic transmission, and they raise the possibility that modulation of mitochondrial conductance by BCL-2 family proteins affects synaptic stability.

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

“…Although yet to be tested, it is conceivable that the ADTinduced increase in Bcl-xl expression in the hippocampus may not correspond with a significant change in the ongoing apoptotic cell death in the hippocampus. Nevertheless, it is well documented that independent of its neurotrophic effects, Bcl-xl influences synaptic stability and modulates neurotransmission (Jonas et al, 2003). Our data raise the possibility that the ADT-mediated Bcl-xl upregulation in the hippocampus may also contribute to synaptic stability in this region.…”

“…An increase in the ratio of pro-vs antiapoptotic proteins is associated with greater vulnerability to apoptotic activation and cell death (Lindsten et al, 2005). Independent of their ability to control cellular survival, Bcl-2 and Bcl-xl antiapoptotic proteins exert pronounced neurotrophic effects (Jonas et al, 2003).…”

Mitochondrial factors with dual roles in death and survival

“…Thus, it appears that Drp1 may support the energetic needs of synaptic transmission independently of its ability to induce cell death. The observation that Bcl-xL, Bak and Bax can alter synaptic activity in mouse and squid model systems, and can colocalize with Drp1 on mitochondria (Karbowski et al, 2002;Fannjiang et al, 2003;Jonas et al, 2003Jonas et al, , 2005a, further suggests that Bcl-2 family proteins may regulate synaptic activity as well as cell death via a functional interaction with Drp1. If true, this would support a model suggesting that all pro-death factors also have pro-survival 'day jobs' (Figure 1).…”

Bcl-XL modulates the differentiation of immortalized human neural stem cells

“…[11][12][13][14] More specifically, Bcl-X L is essential for neuronal survival during brain development and in the adult central nervous system (CNS) (knockout mice and gene-expression studies 15,16 ). In addition to its antiapoptotic role, recent studies have described new roles of Bcl-X L in cell physiology -effects on Ca 2 þ homeostasis and gene expression 17 and synaptic transmission regulation 18 -under not necessarily apoptotic conditions. Several other studies have also described the role of Bcl-X L in the control of cell cycle, 19,20 a process well known to be tightly linked to progression of precursor cells toward neuronal and glia differentiation.…”