Review
Altering BDNF expression by genetics and/or environment: Impact for emotional and depression-like behaviour in laboratory mice

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Abstract

According to the “neurotrophin hypothesis”, brain-derived neurotrophic factor (BDNF) is an important candidate gene in depression. Moreover, environmental stress is known to represent a risk factor in the pathophysiology and treatment of this disease.

To elucidate, whether changes of BDNF availability signify cause or consequence of depressive-like alterations, it is essential to look for endophenotypes under distinct genetic conditions (e.g. altered BDNF expression). Furthermore it is crucial to examine environment-driven BDNF regulation and its effect on depressive-linked features. Consequently, gene × environment studies investigating prospective genetic mouse models of depression in different environmental contexts become increasingly important.

The present review summarizes recent findings in BDNF-mutant mice, which have been controversially discussed as models of depression and anxiety. It furthermore illustrates the potential of environment to serve as naturalistic stressor with the potential to modulate the phenotype in wildtype and mutant mice. Moreover, environment may exert protective effects by regulating BDNF levels as attributed to “environmental enrichment”. The effect of this beneficial condition will also be discussed with regard to probable “curative/therapeutic” approaches.

Introduction

Affective disorders, such as depression and pathological anxiety which are highly concomitant, affect millions of people worldwide. Currently there are only a few effective treatments and there is no satisfying consensus concerning the pathophysiology of these devastating disorders. Former studies support the idea that the neurotrophic system plays a key role in the pathogenesis of depression (Altar, 1999, Calabrese et al., 2009, Hindmarch, 2002, Karege et al., 2002, Lang et al., 2004, Nibuya et al., 1995, Rasmusson et al., 2002, Smith et al., 1995b, Vaidya and Duman, 2001). Particularly mature brain-derived neurotrophic factor (BDNF) as a member of the neurotrophic factor family (including also nerve growth factor (NGF), Neurotrophin-3, and 4-5 (NT-3, NT-4/5) has been discussed to be involved in such processes (Bothwell, 1995). Whether changes of this system are causative or occur as a secondary phenomenon remains questionable though. On the other hand, an up-regulation of neurotrophins has been demonstrated following various antidepressant measures (Angelucci et al., 2000b, D'Sa and Duman, 2002, Duman and Vaidya, 1998, Russo-Neustadt et al., 1999, Russo-Neustadt et al., 2001, Siuciak et al., 1997, Zetterstrom et al., 1998), indicating that these growth factors play a key role in the treatment of affective disorders. Such antidepressant-induced increases in e.g. endogenous BDNF were furthermore accompanied by an enhanced tropomyosine-related kinase B (TrkB) receptor activity, which is required for antidepressant-induced behavioural effects (Saarelainen et al., 2003). However, the exact mechanisms through which antidepressants (which are additionally used to treat other central nervous system (CNS) disorders like chronic pain, phobia or bulimia) exert such effects remain unclear.

A major problem of research on depression to reliably prove such concepts in humans consists in the restriction of systematic approaches, because the detailed investigation of this disease requires the analysis of brain tissue at crucial time points. Consequently, valid and representative animal models are a central tool of experimental psychiatry, especially mouse models, since this species bears the advantage that particular target genes of depression, e.g. BDNF may be manipulated according to the research focus. Further arguments to use mice as model organisms are i) the equivalence to many human genes as well as ii) the similarity of numerous biological and biochemical functions. Nonetheless it is crucial to consider the mouse not only as a model organism, but also as a species by itself with a very complex behavioural repertoire and social organisation that is distinctive concerning gender and strain and therefore results are not directly transferrable to humans. Regarding such restrictions, a very promising mouse model for depression was proposed by Shannon et al. (Gourley and Taylor, 2009), in which prior corticosterone exposure produces a reliable depressive-like state. The two major benefits of this animal are that (i) the same animals may be used after corticosterone wash-out as well as (ii) the easy replication of this strategy between the laboratories, which often states a problem of animal models (Gourley and Taylor, 2009).

Nowadays it is generally accepted that the occurrence of a depressive episode results from a combination of interacting environmental and genetic factors (Mill and Petronis, 2007), which may not be sufficiently illustrated by a very specific approach like the above mentioned corticosterone exposure. Nevertheless such models may help to clarify certain aspects of specific subtypes or endophenotypes of depression, which may be characterized by various symptoms and therefore they also have to be considered in current concepts about the pathophysiology and treatment of depression. As described by many groups addressing such hypotheses by means of animal models, potentially “depressed” rodents are not able to cope/adapt to an environmental challenge (e.g. forced swimming or footshock) which may be attributed to an increased vulnerability to develop depressive-like symptoms (Chourbaji et al., 2008b, Monteggia et al., 2007, Ridder et al., 2005). Such an increased proneness is postulated to be additionally be promoted by aversive (early) experiences such as e.g. maternal separation (Lambas-Senas et al., 2009). Contrary, beneficial experiences (for instance exposure to an enriched environment) may decrease the risk in vulnerable individuals (i.e. in BDNF heterozygous mice) (Chourbaji et al., 2008a).

A malfunction evoking respective “depressive phenotypes” is frequently linked to impairments in neural resilience, with altered expression of so-called plasticity genes such as BDNF, its high-affinity receptor TrkB, or the transcription factor, cAMP response element binding protein (CREB), altering the cascade of events from intracellular signalling to gene expression (for review see (Calabrese et al., 2009)).

Here we review studies considering particularly the role of BDNF in mouse models for depression as well as the impact of various environmental factors (such as housing conditions, social stress, etc.), which may be decisive for the development or cure of depressive-like alterations primarily in rodents, and discuss their clinical implications also in terms of transferability to humans.

Section snippets

The neurotrophin hypothesis of depression

BDNF, NGF, but also NT3, and NT-4/5, are primarily synthesized as 30–35 kDa precursor proteins, which are later on cleaved by pro-convertases at a highly conserved dibasic amino acid cleavage site (Mowla et al., 2001). The resulting neurotrophins share a common basic structure with variable domains determining the binding to their specific receptors and respective biological functioning (Heumann, 1994). Noteworthy, all neurotrophins bind to unselective low-affinity p75, but exclusively interact

Balanced BDNF levels: impact of environmental and genetic factors

According to current theories, different types of environmental stressors (e.g. restraint stress, high density-/or isolated housing) lead to a reduction of neural plasticity (Kim and Yoon, 1998) and decreased BDNF levels in mice (Barrientos et al., 2003), while treatment such as medication with several classes of antidepressants, ECT as well as psychotherapeutic methods, all equally stating external factors, evoke a normalization of BDNF (Castren and Rantamaki, 2008). Thus, the “neurotrophin

BDNF-mutant mice: models for depression?

Genetically modified mice that either over-, or underexpress the neuronal growth factor BDNF theoretically represent valuable tools in the study of the role of BDNF in development, physiology and behaviour (Conover et al., 1995, Croll et al., 1999, Ernfors et al., 1994, Kernie et al., 2000). To assess decisive clinical parameters with regard to depression and emotionality, several meanwhile well-established behavioural paradigms have been created (Table 2). In recent years many lines of mice

BDNF-mutant mice: models for emotionality?

Since transitions are smooth between defined depressive-like characteristics and emotional alterations, it is important to address this point separately. While a major part of the studies performed with BDNF-mutant mice failed to detect obvious depressive phenotypes, there are other studies, which describe BDNF dependent alterations on the emotional level (Table 4).

Such examinations include the observation of aggressive characteristics (e.g. coping in the resident-intruder paradigm) in

Beneficial and detrimental environmental conditions in mice

The quality of environment plays an essential role in the pathophysiology of stress-related diseases such as depression. This has been recognized for human patients, but also for experimental animals. Enriched environment in mutant mice for instance is not only essential to preserve animal welfare and improve the quality of experimental results in animals, which are then able to behave more naturalistic and exploit their behavioural repertoire, but it is equally important to consider in terms

Depression: genes or environment?

Since depression may be “endogenous”, i.e. occurring without any obvious reason, or “reactive”, i.e. evoked by detrimental external factors (e.g. unemployment, death of a beloved person), it is hard to tell, if depression is a more environmentally or genetically induced disease and certainly both aspects affecting the target gene BDNF have to be considered as important in the pathophysiology and treatment of this illness (see Table 5). Furthermore there is a great individual variation

Conclusion and preview

Mouse models for depression state a valuable tool for the investigation of human diseases such as depression. Despite the fact that not all aspects of the human disease can be mimicked by animals (i.e. feelings of guilt, suicide), such models provide important insights into relevant mechanisms involved in pathophysiology and treatment of this disease, and thus facilitate the detailed investigation of endophenotypes or drug-regulated therapeutic mechanisms.

According to current findings and

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