ReviewThe role of BDNF in the pathophysiology and treatment of schizophrenia
Introduction
Schizophrenia (SCZ) is a devastating major mental illness that affects 1% of the world population and is associated with personal and family suffering, high suicide rates and disruption in social functioning (Ross et al., 2006). However, despite much research, the etiology remains poorly understood. While antipsychotic treatment can be very effective, nearly 40 percent of patients achieve only a partial response and 10 percent experience no response at all (Pantelis and Lambert, 2003). Better understanding of the pathophysiological mechanisms is therefore necessary to design better, targeted treatments, to enhance outcomes for these patients.
It is well known that neurotrophic factors, such as Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotrophin-4/5 (NT4/5) promote the growth, differentiation and survival of nerve cells during development and are also involved in the maintenance and plasticity of adult neurons (Huang and Reichardt, 2001; Lewin and Barde, 1996; Maisonpierre et al., 1990). Therefore, primary alterations in the activity of these molecules could lead to inappropriate alterations in cortical circuitry and synaptic transmission in the developing brain, which could then translate into the neural dysfunction underlying psychiatric disorders.
BDNF was the second neurotrophic factor to be characterized after NGF. BDNF is the most widely distributed neutrophin in the CNS and it is highly expressed in the prefrontal cortex (PFC) and hippocampus (Pezawas et al., 2004), where it has been shown to have long-term effects on neuronal survival, differentiation and synaptic plasticity (Pang et al., 2004; Nawa et al., 2000). This review is intended to summarize existing findings about the role of BDNF in the pathophysiology and treatment of SCZ. First, we will review the role of BDNF in synaptic neurotransmission, with special emphasis on GABA and glutamate, two neurotransmitter systems that play a crucial role in the pathophysiology and treatment of SCZ (Lewis et al., 2005), as well as dopamine, since this neurotransmitter has a dominant role in the development of SCZ, regarding the patophysiology, symptoms and medication. Second, we will review the role of BDNF in relation to neuronal plasticity in SCZ. Third, we will review literature evaluating the effects of pharmacological and non-pharmacological treatments in SCZ on BDNF modulation of synaptic transmission which is a differential of this review from others previous published (Buckley et al., 2007, 2011; Green et al., 2011). Finally, we will discuss future studies suggesting novel methods though which BDNF may be targeted as part of treatment for SCZ.
Section snippets
BDNF
BDNF is a basic dimeric polypeptide located on chromosome 11p13. It is initially synthesized as a larger protein precursor and cleaved to form mature BDNF, which is approximately 13 kDa in size (Maisonpierre et al., 1991). BDNF binds at least two receptors, TrkB and p75 (Barbacid, 1995a, Barbacid, 1995b; Chao et al., 1998). TrkB is a tyrosine kinase receptor that, when activated, phosphorylates tyrosine residues and activates a number of intracellular cascades (e.g. calcium influx) (Kaplan and
The role of BDNF in synaptic transmission
Signaling mediated by BDNF and its receptor TrkB can have effects on both excitatory and inhibitory synaptic transmission. The evidence supporting this role comes from two categories of experiments: acute, in which the effects of BDNF are manifested within a few minutes, and chronic, in which effects may take as long as several days to develop.
BDNF exerts neuroprotection and neuroactivation over excitatory and inhibitory neurons, while being produced exclusively in excitatory neurons. BDNF is
BDNF and dopamine
Dopamine (DA) has been strongly implicated in the pathophysiology and treatment of SCZ and there are several known interactions between BDNF and the DA system. BDNF reduces the loss of tyrosine hydroxylase, a marker for dopaminergic neurons, in cell cultures from embryonic rat and human ventral mesencephalon, and protects dopaminergic neurons from neurotoxic agents such as 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+) (Hyman et al., 1991; Spenger et al., 1995; Spina et al.,
BDNF regulation of synaptic Plasticity
Synaptic plasticity is the change in strength in the connectivity between neurons in response to a changing environment. Long-term potentiation (LTP) is a widely studied form of synaptic plasticity, defined as a lasting increase in synaptic strength, following high-frequency stimulation of afferent fibers (Cooke and Bliss, 2006). This process depends initially upon the activation of NMDA-type glutamate receptors, which produces a rapid elevation of calcium concentrations in postsynaptic
BDNF in brain tissue of patients with SCZ
Many studies of BDNF in humans have examined post-mortem tissue from the hippocampus and prefrontal cortex. For example, Takahashi et al. (2000) compared 18 patients diagnosed with SCZ to 36 controls and found increased BDNF levels in the hippocampus and anterior cingulate cortex, but not in the prefrontal nor occipital cortices. Consistent with these findings are several other studies showing reduced TrkB receptor and calbidin-D expression in the hippocampus and the prefrontal cortex in SCZ.
BDNF serum levels in patients with SCZ
It is known that BDNF freely crosses the blood–brain barrier (Pan et al., 1998). In keeping with this observation, it has been shown that levels of BDNF in peripheral serum are strongly correlated with CNS concentrations (Karege et al., 2002). However, the few studies measuring serum BDNF concentrations in patients with SCZ have yielded somewhat inconsistent results (Table 1). The majority of studies reported a significant reduction in serum BDNF levels of chronic and medicated patients with
BDNF and antipsychotic treatments in animals and humans
There have been extensive pre-clinical and clinical studies assessing the effects of antipsychotics on BDNF. For example, Angelucci et al. (2000) found that chronic administration of haloperidol and risperidone significantly decreased BDNF levels in frontal cortex, occipital cortex and hippocampus of rats (Angelucci et al., 2000). Parikh et al. (2004) found reduced BDNF expression in rat hippocampus with haloperidol but not with olanzapine, and Fumagalli et al. (2003) showed similar results in
Effects of electroconvulsive seizures (ECS) on BDNF
The efficacy of electroconvulsive therapy (ECT) for SCZ (Tharyan and Adams, 2002) points to various potential underlying mechanisms, including the impact of repetitive electrical stimulation (either in animals and humans) on BDNF. In rats, many studies have reported a marked increase in BDNF transcripts in response to ECS. Early work was completed by Nibuya et al. (1995) using a rat model where acute (i.e., one treatment) and chronic (i.e., daily treatment for 10 days) ECS were compared.
Electroconvulsive Therapy (ECT) on BDNF
Given the animal data, many have embarked upon parallel studies in human subjects following ECT. To our knowledge, there is only a recently published case report evaluating the effects of ECT on serum BDNF in a case of SCZ. Marinotti et al. (2011) reported a case of a schizophrenic patient with treatment-resistant paranoid-hallucinatory symptoms who was treated with 6 sessions of ECT. BDNF serum levels were measured before each ECT session. The patient presented with gradual improvement of
Effects of repetitive transcranial magnetic stimulation (rTMS) on BDNF
In light of the reported efficacy of rTMS in SCZ and MDD initial work examining the effect of long-term (11 wk) rTMS in rats found that the areas with highest transcriptional upregulation (≥50% increase) included the granule cell layer of the dentate gyrus, as well as the parietal and piriform cortices, with corresponding changes in BDNF-like immunoreactivity (Fitzgerald et al., 2003; Hoffman et al., 2005). As with ECT, depression is the most common indication for this procedure.
Limitations and future directions
Though this article reviews evidence that BDNF may be involved in the pathophysiology of SCZ, a number of limitations should be considered. Although abnormalities in BDNF may contribute to alterations in synaptic transmission and plasticity, which are disrupted in SCZ, studies measuring BDNF in the brain tissue of patients with SCZ have reported inconsistent results. Some studies have found higher levels of BDNF in post-mortem brain samples of patients when compared with controls (Takahashi
Contributors
Gabriela Favalli participated in the conception of the article, the literature review, drafted the first manuscript and wrote the final manuscript. Jennifer Li participated in the literature review and drafted the first manuscript. Paulo Belmonte-de-Abreu reviewed the first manuscript, contributed with the figures and provided scientific supervision. Albert H. C. Wong reviewed the first manuscript, contributed to the literature review and provided scientific supervision. Zafiris J. Daskalakis
Role of the Funding Source
None.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgment
None.
References (130)
- et al.
Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments
Brain Research
(2008) Neurotrophic factors and their receptors
Current Opinion in Cell Biology
(1995)- et al.
Electroconvulsive Therapy (ECT) increases serum Brain Derived Neurotrophic Factor (BDNF) in drug resistant depressed patients
European Neuropsychopharmacology
(2006) - et al.
Brain derived neurotropic factor in first-episode psychosis
Schizophrenia Research
(2007) - et al.
BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons
Molecular and Cellular Neuroscience
(2007) - et al.
Role of neurotrophic factors in depression
Current Opinion in Pharmacology
(2007) - et al.
Neurotrophin receptors: mediators of life and death
Brain Research Reviews
(1998) - et al.
Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration
Brain Research
(2002) - et al.
Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain
Neuropharmacology
(2003) - et al.
Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses
Schizophrenia Research
(2001)
Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): a pilot study in drug resistant depressed patients
Neuroscience Letters
Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder
Neuroscience Letters
Site-Specific antidepressant effects of Repeated Subconvulsive electrical stimulation: potential Rle of brain-derived neurotrophic factor
Biological Psychiatry
Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia
Biological Psychiatry
Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics
Journal of Psychiatry Research
Chronic mild stress inhibits BDNF expression and CREB activation in the dentate gyrus but not in the hippocampus proper
Pharmacology, Biochemistry and Behavior
Critical role of brain-derived neurotrophic factor in mood disorders
Brain Research Reviews
Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample
Biological Psychiatry
Rat fetal ventral mesencephalon grown as solid tissue cultures: influence of culture time and BDNF treatment on dopamine neuron survival and function
Brain Research
Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients
Journal of Psychiatry Research
Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia
Schizophrenia Research
Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains
Progress in Neuropsychopharmacology and Biological Psychiatry
The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels
Brain Research
Neurotrophin signal transduction in the nervous system
Current Opinion in Neurobiology
Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets
Neuroscience Letters
Repeated electroconvulsive stimuli have long-lasting effects on hippocampal BDNF and decrease immobility time in the rat forced swim test
Life Sciences
Developmental pathology, dopamine, stress and schizophrenia
International Journal of Developmental Neuroscience
NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression
Neuron
Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations
Genomics
Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization
Neuron
Essential role for TrkB receptors in hippocampus-mediated learning
Neuron
Mechanism of TrkB-mediated hippocampal long-term potentiation
Neuron
Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study
Progress in Neuropsychopharmacology and Biological Psychiatry
Increased synaptic inhibition in dentate gyrus of mice with reduced levels of endogenous brain-derived neurotrophic factor
Neuroscience
Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients
Schizophrenia Research
Transport of brain-derived neurotrophic factor across the blood-brain barrier
Neuropharmacology
Olanzapine counteracts reduction of brain-derived neurotrophic factor and TrkB receptors in rat hippocampus produced by haloperidol
Neuroscience Letters
Effects of quetiapine on the brain-derived neurotrophic factor expression in the hippocampus and neocortex of rats
Neuroscience Letters
Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats
Journal of Psychiatry Research
Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice
Neuron
Plasma Brain-Derived Neurotrophic Factor in treatment-resistant depressed patients receiving electroconvulsive therapy
European Neuropsychopharmacology
Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus
Schizophrenia Research
Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment
Progress in Neuropsychopharmacology and Biological Psychiatry
Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications
Journal of Psychiatry Research
Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways
The Journal of Neuroscience
Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration
Journal of Neuroscience Research
Electroconvulsive stimuli alter the regional concentrations of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in adult rat brain
The Journal of ECT
Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo
The European Journal of Neuroscience
Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta
The Journal of Neuroscience
Structural and functional properties of the TRK family of neurotrophin receptors
Annals of New York Academy of Science
Cited by (159)
Cotransplantation of NSCs and ethyl stearate promotes synaptic plasticity in PD rats by Drd1/ERK/AP-1 signaling pathway
2024, Journal of EthnopharmacologyA protocol for establishing a male G×E schizophrenia mouse model
2022, STAR ProtocolsAre the measurement structures of the Traditional Chinese Dispositional Flow Scale-2 equivalent between schizophrenic patients and healthy subjects?
2022, Journal of the Formosan Medical AssociationNeurobehavioral and neurodevelopmental profiles of a heuristic genetic model of differential schizophrenia- and addiction-relevant features: The RHA vs. RLA rats
2021, Neuroscience and Biobehavioral ReviewsThe role of integrin beta in schizophrenia: A preliminary exploration
2023, CNS Spectrums