Developmental expression of brain derived neurotrophic factor mRNA by neurons of fetal and adult monkey prefrontal cortex

doi:10.1016/0165-3806(92)90103-4

Developmental Brain Research

Volume 70, Issue 1, 20 November 1992, Pages 53-63

https://doi.org/10.1016/0165-3806(92)90103-4 Get rights and content

Abstract

In situ hybridization histochemistry with labeled cRNA probes complementary to monkey brain derived neurotrophic factor (BDNF) mRNAs has been used to study the cellular localization and expression of this neurotrophin in the prefrontal cerebral cortex of fetal and adult monkeys. Expression could not be detected in prefrontal cortex before the 121st fetal day. Thereafter, in fetal life and in adulthood BDNF mRNA could be detected primarily in large, putative pyramidal cells of layers III and VI throughout the prefrontal cortex. The temporal course and cellular localization of BDNF expression suggests its association with the development and stabilization of specific connections in regions of cortex that display marked functional plasticity.

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Of note, other studies have also shown that brain BDNF levels may be increased by glutamatergic activation,28–30 suggesting an interaction between BDNF and glutamate in synaptic signaling. In addition, evidence of the regulatory action of glutamate-induced BDNF on neuronal connectivity was first demonstrated in the prefrontal cortex of primates.31 The role of these cellular mechanisms in depression has been investigated by researchers over the last few years, and many studies have reported evidence that links glutamatergic activity, BDNF expression, and synaptic connectivity.32
Emerging evidence suggests that dysfunctions in glutamatergic signaling are associated with the pathophysiology of depression. Several molecules that act on glutamate binding sites, so-called glutamatergic modulators, are rapid-acting antidepressants that stimulate synaptogenesis. Their antidepressant response involves the elevation of both extracellular glutamate and brain-derived neurotrophic factor (BDNF) levels, as well as the postsynaptic activation of the mammalian target of rapamycin complex 1. The mechanisms involved in the antidepressant outcomes of glutamatergic modulators, including ketamine, suggest that astrocytes must be considered a cellular target for developing rapid-acting antidepressants. It is well known that extracellular glutamate levels and glutamate intrasynaptic time-coursing are maintained by perisynaptic astrocytes, where inwardly rectifying potassium channels 4.1 (Kir4.1 channels) regulate both potassium and glutamate uptake. In addition, ketamine reduces membrane expression of Kir4.1 channels, which raises extracellular potassium and glutamate levels, increasing postsynaptic neural activities. Furthermore, inhibition of Kir4.1 channels stimulates BDNF expression in astrocytes, which may enhance synaptic connectivity. In this review, we discuss glutamatergic modulators’ actions in regulating extracellular glutamate and BDNF levels, and reinforce the importance of perisynaptic astrocytes for the development of novel antidepressant drugs.
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Consequently, the presence of BDNF mRNA in rodents correlates very well with the site of synthesis of BDNF protein in specific tissues and cells (Conner et al., 1997). The mRNA for BDNF is widely distributed throughout the central nervous system (CNS) of rat and mice, including brain regions like the hippocampal formation (Conner et al., 1997; Connor and Dragunow, 1998; Ernfors et al., 1990; Hofer et al., 1990; Phillips et al., 1990; Schmidt-Kastner et al., 1996; Son and Winzer-Serhan, 2009; Wetmore et al., 1990, 1991), cerebral cortex (Conner et al., 1997; Hofer et al., 1990; Huntley et al., 1992; Phillips et al., 1990; Schmidt-Kastner et al., 1996; Timmusk et al., 1993; Wetmore et al., 1990, 1991), thalamus (Conner et al., 1997; Hofer et al., 1990; Schmidt-Kastner et al., 1996; Timmusk et al., 1993), hypothalamus (Conner et al., 1997; Hofer et al., 1990; Liao et al., 2012), olfactory bulb (Conner et al., 1997; Hofer et al., 1990; Phillips et al., 1990), amygdala (Conner et al., 1997; Phillips et al., 1990; Schmidt-Kastner et al., 1996; Wetmore et al., 1991), cerebellar granule cell layer (Hofer et al., 1990; Vazquez-Sanroman et al., 2013; Wetmore et al., 1990) and spinal cord (Conner et al., 1997; Hofer et al., 1990; Luo et al., 2001). In the hippocampus a similar distribution of BDNF mRNA was described for rodents and primates (Phillips et al., 1990).
Overwhelming evidence collected since the early 1990's strongly supports the notion that BDNF is among the key regulators of synaptic plasticity in many areas of the mammalian central nervous system. Still, due to the extremely low expression levels of endogenous BDNF in most brain areas, surprisingly little data i) pinpointing pre- and postsynaptic release sites, ii) unraveling the time course of release, and iii) elucidating the physiological levels of synaptic activity driving this secretion are available. Likewise, our knowledge regarding pre- and postsynaptic effects of endogenous BDNF at the single cell level in mediating long-term potentiation still is sparse. Thus, our review will discuss the data currently available regarding synaptic BDNF secretion in response to physiologically relevant levels of activity, and will discuss how endogenously secreted BDNF affects synaptic plasticity, giving a special focus on spike timing-dependent types of LTP and on mossy fiber LTP. We will attempt to open up perspectives how the remaining challenging questions regarding synaptic BDNF release and action might be addressed by future experiments.
This article is part of the Special Issue entitled ‘BDNF Regulation of Synaptic Structure, Function, and Plasticity’.
Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine
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As such, it is likely that after repeated amphetamine, BDNF-containing mPFC neurons preferentially, but not exclusively, innervate the VTA. Because BDNF is only present in prefrontal pyramidal neurons during adulthood (Huntley et al., 1992), we infer that the observed increase in mPFC BDNF after amphetamine occurred exclusively in glutamate-containing projection neurons, and not GABA-containing interneurons. Consistent with this, the VTA receives more glutamatergic innervation from the PFC than any other region (Geisler et al., 2007).
Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague–Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.
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The brain-derived neurotrophic factor (BDNF) gene contains multiple 5′ promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro (∼32 kDa), pro (∼28 kDa) and mature (∼14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia.
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Although genetically closely related AB-Halle (ABH) and AB-Gatersleben (ABG) mice inbred strains differ in activity and aggressive behaviour. These behavioural traits have been observed especially in response to social challenges, where ABH mice develop a highly aggressive and active behaviour, which cannot be observed in their ABG counterparts. In contrast to ABG mice, basal brain serotonin, dopamine and noradrenaline concentrations in ABH mice are low but highly stimulated by social challenges. Since brain-derived neurotrophic factor (BDNF) modulates central neurotransmitter systems and has been involved in aggressive and activity behaviour, we studied specific concentrations of BDNF and NGF protein in several brain regions of ABG and ABH mice.
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Citation Excerpt :
As working memory dysfunction is central to the pathology of schizophrenia, we specifically note that expression of BDNF and TrkB is significantly reduced in the dorsolateral PFC of schizophrenic patients (Weickert et al., 2003, 2005; Hashimoto et al., 2005). In monkeys, BDNF mRNA is highly expressed in large pyramidal neurons of layers III and IV throughout the PFC of fetal and adult monkeys (Huntley et al., 1992). Correspondingly, full-length TrkB receptor immunoreactivity is also expressed in pyramidal cells of layers II, III, V, and VI, and is developmentally regulated (Hayashi et al., 2000).
Working memory is the ability to maintain representations of task-relevant information for short periods of time to guide subsequent actions or make decisions. Neurons of the prefrontal cortex exhibit persistent firing during the delay period of working memory tasks. Despite extensive studies, the mechanisms underlying this persistent neural activity remain largely obscure. The neurotransmitter systems of dopamine, NMDA, and GABA have been implicated, but further investigations are necessary to establish their precise roles and relationships. Recent research has suggested a new component: brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB. We review the research on persistent activity and suggest that BDNF/TrkB signaling in a distinct class of interneurons plays an important role in organizing persistent neural activity at the single-neuron and network levels.

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^∗: Present address: Department of Neurobiology, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

^∗∗: Present address: Department of Neuroscience, University of Virginia, School of Medicine, Box 230 Medical Center, Charlottesville, VA 22908, USA.

^∗∗∗: Present address:Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 3224, USA.

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Research reportDevelopmental expression of brain derived neurotrophic factor mRNA by neurons of fetal and adult monkey prefrontal cortex

Abstract

Neuron

Lancet

Neuron

Dev. Brain Res.

Neuron

J. Biol. Chem.

Dev. Brain Res.

Neuroscience

Neuron

FEBS Lett.

Brain Res.

Brain Res.

FEBS Lett.

Cell

Neuroscience

Brain Res.

Dev. Biol.

Neuron

J. Biol. Chem.

Brain Res.

Mol. Brain Res.

Neuron

Neuron

Neuron

Neuron

Trends Neurosci.

Exp. Neurol.

Neuroscience

Brain Res.

Brain Res. Bull.

Dev. Brain Res.

Nerve growth factor receptor immunoreactivity is transiently associated with the subplate neurons of the mammalian cerebral cortex

Purification of a new neurotrophic factor from mammalian brain

EMBO J.

The cholinergic hypothesis of geriatic memory dysfunction

Science

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J. Neurosci.

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J. Neurosci.

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Science

Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders

Arch. Gen. Psychiatry

Dopamine receptor binding predicts clinical and pharmacological potencies of anti-schizophrenic drugs

Science

Development and survival of neurons in dissociated fetal mesencephalic serum-free cell cultures: I. effects of cell density and of an adult mammalian striatal-derived neuronotrophic factor (SDNF)

J. Neurosci.

Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor

Nature

Synaptic excitation of neurones in area 17 of the cat by intracortical axon collaterals of corticogeniculate cells

J. Physiol.

Cells that express brain-derived neurotrophic factor mRNA in the developing postnatal rat brain

Eur. J. Neurosci.

Limbic seizures increase neuronal production of messenger RNA for nerve-growth factor

Science

Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys

J. Comp. Neurol.

Developmental and plasticity of primate frontal association cortex

Circuitry of the prefrontal cortex and the regulation of behavior by representational knowledge

Prenatal removal of frontal association cortex in the fetal rhesus monkey: anatomical and functional consequences in postnatal life

Brain Res.

Research report
Developmental expression of brain derived neurotrophic factor mRNA by neurons of fetal and adult monkey prefrontal cortex