Review
Psychiatric vulnerability: Suggestions from animal models and role of neurotrophins

https://doi.org/10.1016/j.neubiorev.2008.09.004Get rights and content

Abstract

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well-studied neurotrophins involved in the neurogenesis, differentiation, growth and maintenance of selected peripheral and central populations of neuronal cells during development and at adulthood. Neurotrophins, in concert to hypothalamic–pituitary–adrenal (HPA) axis, play a key role in modulating brain plasticity and behavioral coping, especially during ontogenetic critical periods, when developing brain is particularly sensitive to external stimulations. Indeed, early life events, such psychophysical stress, affect NGF and BDNF levels, and induce dysregulation of the HPA axis. Thus, early life experiences can affect brain development, contributing to shape interindividual differences in vulnerability to stress or psychiatric disorders. At adulthood, intermale aggressive interactions in mice, representing a psychosocial stressful condition, has been shown to markedly alter NGF and BDNF levels both in plasma as well as in selected brain areas, including the hypothalamus and hippocampus. These results have been extended to humans, showing that blood NGF levels are enhanced in psychological contexts mainly associated to anxiety and fear, such as first skydiving experience. Recent studies indicate a role for neurotrophins also in vulnerability and resilience to stress-related neuropsychiatric disorders. Overall, these findings suggest a role of neurotrophins as factors mediating both short- and long-term experience effects on brain structure and function.

Section snippets

NGF and psychiatric diseases

In the last decades, after the impulse and the mass communication explosion that followed the seminal work of the neuroscientist Rita Levi-Montalcini (awarded the Nobel Prize in 1986), the studies on the role exerted by neurotrophins (NTs) on central nervous system (CNS) and behavior have greatly increased.

In November 1986, the semi-popular magazine “New Scientist” entitled “Nerve growth factor—a potential cure-all?” in its “News and Views”, where the idea that nerve growth factor (NGF) action

The “global vulnerability”

Progressive alteration of NTs levels in blood or and/or neural tissue may be responsible for individual vulnerability to psychiatric diseases. As an example about vulnerability in general, we selected the classical case of diabetes, a disease in which physiological, weakly or heavily pathological, with intermediate (paraphysiological) levels of insulin, vary along a gradient of insulin levels in the bloodstream (see Fig. 1).

Presently, diabetes is viewed as a morbid affliction not only

BDNF also modulates brain plasticity and coping

BDNF was described first in 1982 (about 30 years later the NGF discovery), as the culmination of studies mainly performed at the Biozentrum of the University of Basel (Switzerland). Although several investigators have participated, the course of BDNF discovery has been largely charted by Yves-Alain Barde, with the unflinching support of Hans Thoenen (Barde et al., 1982).

In contrast to NGF and NT-3 transcripts, which are abundant in peripheral tissues, BDNF mRNA is predominantly synthesized in

Clinical relevance of the neurotrophins and therapeutic perspectives

Accumulating evidences from clinical, preclinical and animal studies indicate a key role for NTs in the pathophysiology of psychiatric diseases. Indeed, as already reported in this review, low plasma levels of NGF were found in schizophrenic patients (Bersani et al., 1999, Parikh et al., 2003), while low serum BDNF levels have been reported in both schizophrenic patients and patients with depressive disorders (Karege et al., 2002, Toyooka et al., 2002). A recent study performed on patients

General conclusion

NTs are key factors in mediating both short- and long-term experience effects on brain structure and function. However, much remains to be understood about the role played by NGF and BDNF on CNS targets regulating brain plasticity and behavioral coping both during development and at adulthood.

Moreover, further insight into physiological processes controlled by NTs may eventually yield innovative therapeutic tools for psychopathologies, including innovative peptidergic drugs. Indeed, data

Acknowledgments

Work supported by the ISS-NIH Collaborative Project (0F14) to EA and FC and by the Italian Ministry of Health, Ricerca Finalizzata ex art. 12 - 2006, to EA. The authors thank Giovanni Dominici and Simona Miletta for technical support, and Francesca Cirulli, Daniela Santucci, Igor Branchi, Walter Adriani and Giovanni Laviola for useful comments on the manuscript.

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