Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the ...formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.
This article is part of the Special Issue entitled ‘BDNF Regulation of Synaptic Structure, Function, and Plasticity’.
•BDNF regulates transcription and the transport of mRNAs along dendrites.•BDNF-TrkB signaling upregulates translation activity at the synapse.•The effects of BDNF on translation may also be mediated through regulation of miRNAs.•BDNF also induces transcription- and translation-independent responses at the synapse.•Local protein synthesis induced by BDNF contributes to long-term synaptic plasticity and memory formation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Abstract The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of activity-dependent plasticity at excitatory synapses in the mammalian central nervous system. In ...particular, much attention has been given to the role of the neurotrophin in the regulation of hippocampal long-term potentiation (LTP), a sustained enhancement of excitatory synaptic strength believed to underlie learning and memory processes. In this review we summarize the evidence pointing to a role for BDNF in generating functional and structural changes at synapses required for both early- and late phases of LTP in the hippocampus. The available information regarding the pre- and/or postsynaptic release of BDNF and action of the neurotrophin during LTP will be also reviewed. Finally, we discuss the effects of BDNF on the synaptic proteome, either by acting on the protein synthesis machinery and/or by regulating protein degradation by calpains and possibly by the ubiquitin-proteasome system (UPS). This fine-tuned control of the synaptic proteome rather than a simple upregulation of the protein synthesis may play a key role in BDNF-mediated synaptic potentiation. This article is part of a Special Issue entitled SI: Brain and Memory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Mitochondria are present in the pre- and post-synaptic regions, providing the energy required for the activity of these very specialized neuronal compartments. Biogenesis of synaptic mitochondria ...takes place in the cell body, and these organelles are then transported to the synapse by motor proteins that carry their cargo along microtubule tracks. The transport of mitochondria along neurites is a highly regulated process, being modulated by the pattern of neuronal activity and by extracellular cues that interact with surface receptors. These signals act by controlling the distribution of mitochondria and by regulating their activity. Therefore, mitochondria activity at the synapse allows the integration of different signals and the organelles are important players in the response to synaptic stimulation. Herein we review the available evidence regarding the regulation of mitochondrial dynamics by neuronal activity and by neuromodulators, and how these changes in the activity of mitochondria affect synaptic communication.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
AMPA-type receptors for the neurotransmitter glutamate are very dynamic entities, and changes in their synaptic abundance underlie different forms of synaptic plasticity, including long-term synaptic ...potentiation (LTP), long-term depression (LTD) and homeostatic scaling. The different AMPA receptor subunits (GluA1-GluA4) share a common modular structure and membrane topology, and their intracellular C-terminus tail is responsible for the interaction with intracellular proteins important in receptor trafficking. The latter sequence differs between subunits and contains most sites for post-translational modifications of the receptors, including phosphorylation, O-GlcNAcylation, ubiquitination, acetylation, palmitoylation and nitrosylation, which affect differentially the various subunits. Considering that each single subunit may undergo modifications in multiple sites, and that AMPA receptors may be formed by the assembly of different subunits, this creates multiple layers of regulation of the receptors with impact in synaptic function and plasticity. This review discusses the diversity of mechanisms involved in the post-translational modification of AMPA receptor subunits, and their impact on the subcellular distribution and synaptic activity of the receptors.
Neuronal excitability depends on the balance between inhibitory and excitatory neurotransmission, which in the CNS are mainly mediated by GABA and glutamate respectively. The plasticity of ...glutamatergic synapses and the underlying molecular mechanisms have been characterized to a large extent. In comparison, much less is known regarding the plasticity of GABAergic synapses, which is also important in the maintenance of the excitatory/inhibitory balance. GABAergic synapses, similarly to the glutamatergic synapses, adjust their strength depending on the pattern of neuronal activity. These alterations take place in the pre- and postsynaptic compartments, and short- and long-term alterations have been described. At the postsynaptic level the plasticity of inhibitory synapses is largely mediated by modulation of the expression, localization and function of GABA
receptors, by mechanisms involving the participation of scaffold proteins and structural molecules. This review is focused on the key mechanisms that regulate GABA
receptor trafficking in response to alterations in neuronal activity or to stimulation of plasma membrane receptors. These alterations in GABAergic neurotransmission are important in the refinement of the pattern of activity of neuronal networks. In this work, we review some of the mechanisms contributing to the plasticity of inhibitory synapses in the CNS, focusing on the regulation of GABA
receptor (GABA
R) trafficking in response to alterations in neuronal activity or to stimulation of different classes of plasma membrane-associated receptors. Alterations in these mechanisms are important in the refinement of neuronal network activity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate ...release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT) 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7), indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during embryonic and neonatal development in contrast to adult tissue expressing only VGLUT1. These results suggest that BDNF regulates VGLUT expression during development and its effect on VGLUT1 may contribute to enhance glutamate release in LTP.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuronal excitability depends on the balance between inhibitory and excitatory neurotransmission, which in the CNS are mainly mediated by GABA and glutamate respectively. The plasticity of ...glutamatergic synapses and the underlying molecular mechanisms have been characterized to a large extent. In comparison, much less is known regarding the plasticity of GABAergic synapses, which is also important in the maintenance of the excitatory/inhibitory balance. GABAergic synapses, similarly to the glutamatergic synapses, adjust their strength depending on the pattern of neuronal activity. These alterations take place in the pre‐ and postsynaptic compartments, and short‐ and long‐term alterations have been described. At the postsynaptic level the plasticity of inhibitory synapses is largely mediated by modulation of the expression, localization and function of GABAA receptors, by mechanisms involving the participation of scaffold proteins and structural molecules. This review is focused on the key mechanisms that regulate GABAA receptor trafficking in response to alterations in neuronal activity or to stimulation of plasma membrane receptors. These alterations in GABAergic neurotransmission are important in the refinement of the pattern of activity of neuronal networks.
In this work, we review some of the mechanisms contributing to the plasticity of inhibitory synapses in the CNS, focusing on the regulation of GABAA receptor (GABAAR) trafficking in response to alterations in neuronal activity or to stimulation of different classes of plasma membrane‐associated receptors. Alterations in these mechanisms are important in the refinement of neuronal network activity.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
In this work, we review some of the mechanisms contributing to the plasticity of inhibitory synapses in the CNS, focusing on the regulation of GABAA receptor (GABAAR) trafficking in response to alterations in neuronal activity or to stimulation of different classes of plasma membrane‐associated receptors. Alterations in these mechanisms are important in the refinement of neuronal network activity.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
GABAA receptors (GABAAR) are the major players in fast inhibitory neurotransmission in the central nervous system (CNS). Regulation of GABAAR trafficking and the control of their surface expression ...play important roles in the modulation of the strength of synaptic inhibition. Different pieces of evidence show that alterations in the surface distribution of GABAAR and dysregulation of their turnover impair the activity of inhibitory synapses. A diminished efficacy of inhibitory neurotransmission affects the excitatory/inhibitory balance and is a common feature of various disorders of the CNS characterized by an increased excitability of neuronal networks. The synaptic pool of GABAAR is mainly controlled through regulation of internalization, recycling and lateral diffusion of the receptors. Under physiological condition these mechanisms are finely coordinated to define the strength of GABAergic synapses. In this review, we focus on the alteration in GABAAR trafficking with an impact on the function of inhibitory synapses in various disorders of the CNS. In particular we discuss how similar molecular mechanisms affecting the synaptic distribution of GABAAR and consequently the excitatory/inhibitory balance may be associated with a wide diversity of pathologies of the CNC, from psychiatric disorders to acute alterations leading to neuronal death. A better understanding of the cellular and molecular mechanisms that contribute to the impairment of GABAergic neurotransmission in these disorders, in particular the alterations in GABAAR trafficking and surface distribution, may lead to the identification of new pharmacological targets and to the development of novel therapeutic strategies.
Abstract
Cell culture models are important tools to study epileptogenesis mechanisms. The aim of this work was to characterize the spontaneous and synchronized rhythmic activity developed by cultured ...hippocampal neurons after transient incubation in zero Mg
2+
to model
Status Epilepticus
. Cultured hippocampal neurons were transiently incubated with a Mg
2+
-free solution and the activity of neuronal networks was evaluated using single cell calcium imaging and whole-cell current clamp recordings. Here we report the development of synchronized and spontaneous Ca
2+
i
transients in cultured hippocampal neurons immediately after transient incubation in a Mg
2+
-free solution. Spontaneous and synchronous Ca
2+
i
oscillations were observed when the cells were then incubated in the presence of Mg
2+
. Functional studies also showed that transient incubation in Mg
2+
-free medium induces neuronal rhythmic burst activity that was prevented by antagonists of glutamate receptors. In conclusion, we report the development of epileptiform-like activity, characterized by spontaneous and synchronized discharges, in cultured hippocampal neurons transiently incubated in the absence of Mg
2+
. This model will allow studying synaptic alterations contributing to the hyperexcitability that underlies the development of seizures and will be useful in pharmacological studies for testing new drugs for the treatment of epilepsy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The excessive extracellular accumulation of glutamate in the ischemic brain leads to an overactivation of glutamate receptors with consequent excitotoxic neuronal death. Neuronal demise is largely ...due to a sustained activation of NMDA receptors for glutamate, with a consequent increase in the intracellular Ca(2+) concentration and activation of calcium- dependent mechanisms. Calpains are a group of Ca(2+)-dependent proteases that truncate specific proteins, and some of the cleavage products remain in the cell, although with a distinct function. Numerous studies have shown pre- and post-synaptic effects of calpains on glutamatergic and GABAergic synapses, targeting membrane- associated proteins as well as intracellular proteins. The resulting changes in the presynaptic proteome alter neurotransmitter release, while the cleavage of postsynaptic proteins affects directly or indirectly the activity of neurotransmitter receptors and downstream mechanisms. These alterations also disturb the balance between excitatory and inhibitory neurotransmission in the brain, with an impact in neuronal demise. In this review we discuss the evidence pointing to a role for calpains in the dysregulation of excitatory and inhibitory synapses in brain ischemia, at the pre- and post-synaptic levels, as well as the functional consequences. Although targeting calpain-dependent mechanisms may constitute a good therapeutic approach for stroke, specific strategies should be developed to avoid non-specific effects given the important regulatory role played by these proteases under normal physiological conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
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