Elsevier

Progress in Neurobiology

Volume 112, January 2014, Pages 80-99
Progress in Neurobiology

Stress and trauma: BDNF control of dendritic-spine formation and regression

https://doi.org/10.1016/j.pneurobio.2013.10.005Get rights and content

Highlights

  • Epigenetic mechanisms are associated with repression and activation of BDNF exon IV transcripts.

  • Epigenetic mechanisms are involved in the consolidation of memory after a psychologically stressful challenge.

  • Histone lysine methylation mediates transcriptional regulation of genes, such as for BDNF, in the hippocampus.

  • The ERK1/2 pathway is important for the upregulation of miR132 during BDNF stimulation.

  • Changes in BDNF transcription is the major causal agent for the changes in spine density following stress.

Abstract

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress.

Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines.

Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.

Introduction

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth (see Section 4 below), these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF, as described in Section 2. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes (see Section 2.4). Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress, and this is investigated in Section 3.

Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. This possibility is surveyed in Sections 4 BDNF control of dendritic spines, 5 BDNF/TrkB control of dendritic spines modulated by glucocorticoid and mineralocorticoid receptors, first through a description of these downstream pathways (Section 4) and then of how they are modulated by steroids (Section 5).

Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact (Govindarajan et al., 2006). It seems then that CRF does have a role to play in determining BDNF control of dendritic spines and this is investigated in Section 6. Finally, other receptors besides that of CRFR1 also modulate the expression of the BDNF gene, including those for cannabinoids, serotonin, and glutamate and as such their roles are also considered (in Sections 7 Cannabinoid (receptor CB1) modulation of BDNF gene transcription and BDNF/TrkB control of dendritic spines, 8 Serotonin transporter (SERT) modulation of BDNF gene transcription and BDNF/TrkB control of dendritic spines).

This review concludes with the suggestion (see Section 9) that the core issue in disabilities related to traumatic stress arises from failure of the normal operation of various reasonably well identified neural networks as a consequence of the inappropriate regression or growth of dendritic spines that subserve these networks. It follows that the critical translational effort should be to intervene in such a way as to prevent these changes or to reconstitute the normal spine densities once the stress effects have taken place. This being the case it is of paramount importance to identify details of the mechanisms by which different steroid receptors differentially modulate BDNF gene expression.

Section snippets

The BDNF gene

The rat BDNF gene consists of four short 5′ exons and a 3′ exon encoding the mature BDNF protein (Timmusk et al., 1993). Quantitative PCR analysis of BDNF mRNA containing these five upstream exons indicates that each of the alternative transcripts is most abundant in the hippocampus, intermediate in the substantia nigra and cerebellum and least abundant in the striatum, although the magnitude of these differences in expression varies indicating that BDNF gene transcription in the mature brain

BDNF gene transcription controlled by epigenetic changes

BDNF expression is under the control of GR (Suri and Vaidya, 2013). BDNF is subject to epigenetic control, that is to changes in BDNF gene expression that remain stable during cell divisions, but do not involve changes in the BDNF DNA sequence (Spijker and van Rossum, 2012). This has been most thoroughly investigated for the nine non-coding exons and common coding exon of the rodent BDNF gene (Aid et al., 2007, Roth and Sweatt, 2011, Timmusk et al., 1993).

BDNF control of dendritic spines

BDNF changes spine morphology in a synaptic activity-dependent manner, so that with normal transmission BDNF increases the properties of stubby, type-I spines, with miniature synaptic potentials capable in the presence of BDNF to establish defined morphological spine types (Tyler and Pozzo-Miller, 2003). Spines in the absence of spontaneous electrical activity are significantly smaller than normal, at least on the proximal domain of dendrites (Harvey et al., 2005). On the other hand,

Glucocorticoid and mineralocorticoid modulation of ERK and GTPase pathways for control of dendritic spines: the GR-ERK-BDNF-synaptic proteins

An increase in synaptic proteins in developing cortical neurons due to BDNF is reduced by dexamethasone via suppression of ERK-signaling through src homology – 2 domain – containing phosphatase 2 (Shp2) and TrkB interaction (Fig. 8) (Kumamaru et al., 2011, Kumamaru et al., 2008, Numakawa et al., 2010, Numakawa et al., 2013). Corticosterone administered for one hour increases spine density of hippocampal pyramidal neurons, whereas GR antagonists and activation blockade of kinases PKA, PKC, P13K

BDNF/TrkB control of dendritic spines modulated by corticotropin releasing factor (hormone)

As described above, a canonical role for the glucocorticoids in stress-induced changes of dendritic spines is now well established. However recent studies using forebrain specific knockout of CRFR1 suggest that, even in the presence of a functional glucocorticoid system, the absence of CRFR attenuates the detrimental affects of chronic stress on dendritic arborization and spines (Chen et al., 2012b). It appears therefore that CRF, besides GR, have a role to play in determining dendritic spine

Cannabinoid (receptor CB1) modulation of BDNF gene transcription and BDNF/TrkB control of dendritic spines

Endocannabinoids (eCBs) modulate the levels of BDNF in certain parts of the brain. Thus endocannabinoid receptor 1 (eCBR1) knockout mice have a decreased BDNF level in the hippocampus but not in the amygdala or neocortex. This may be specific to BDNF as neither nerve growth factor nor neurotrophic factor-3 are affected in these knockout mice (Aso et al., 2008). The principal cannabinoids at synapses are anandamide (AEA) and 2-arachidonoylglycerol. Metabolism of AEA is by fatty acid amide

Serotonin transporter (SERT) modulation of BDNF gene transcription and BDNF/TrkB control of dendritic spines

Modification of serotonin reuptake transport, with inhibitors such as fluoxetine, augments BDNF exon I mRNA levels in the BLA as well as in the hippocampus (Karpova et al., 2011). This augmentation is lost and replaced by a decrease in BDNF levels if the mice are homozygous for the BDNF Val66Met SNP (Bath et al., 2012).

A better outcome is obtained for erasing fear memories in PTSD subjects than using d-cycloserine if a combination is used of extinction training with chronic fluoxetine treatment

Conclusion

The following points are suggested by the present review on identifying the changes in dendritic spine synapses in neural networks under stress, the mechanisms that drive these, and how these networks can be reinstated to normality.

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