Yves Larmet

Protective effects of brain-derived neurotrophic factor on the development of hippocampal kindling in the rat

Recent data have suggested the involvement of neurotrophins in the cascade of events occurring during seizure development. In particular, expression of both brain-derived neurotrophic factor (BDNF) and its receptor mRNAs increases in different brain structures after convulsive seizures. The physiological significance of this increase was investigated by chronic intrahippocampal perfusion of BDNF in the model of dorsal hippocampal kindling in the rat. A 7 day perfusion of BDNF, in the region of the stimulating electrode, blocked the development of kindling during the perfusion period and for the following 15 days. These results provide in vivo evidence for a protective role of BDNF in the regulation of plasticity involved in epileptogenesis in adult brain.

Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy

Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated with the pathophysiology of MTLE are known to be regulated by brain-derived neurotrophic factor (BDNF) in the healthy brain and an excess of this neurotrophin could therefore play a critical role in MTLE development. However, such a function remains controversial as other studies revealed that BDNF could, on the contrary, exert protective effects regarding epilepsy development. In the present study, we further addressed the role of increased BDNF/TrkB signaling on the progressive development of hippocampal seizures in the mouse model of MTLE obtained by intrahippocampal injection of kainate. We show that hippocampal seizures progressively developed in the injected hippocampus during the first two weeks following kainate treatment, within the same time-frame as a long-lasting and significant increase of BDNF expression in dentate granule cells. To determine whether such a BDNF increase could influence hippocampal epileptogenesis via its TrkB receptors, we examined the consequences of (i) increased or (ii) decreased TrkB signaling on epileptogenesis, in transgenic mice overexpressing the (i) TrkB full-length or (ii) truncated TrkB-T1 receptors of BDNF. Epileptogenesis was significantly facilitated in mice with increased TrkB signaling but delayed in mutants with reduced TrkB signaling. In contrast, TrkB signaling did not influence granule cell dispersion, an important feature of this mouse model which is also observed in most MTLE patients. These results suggest that an increase in TrkB signaling, mediated by a long-lasting BDNF overexpression in the hippocampus, promotes epileptogenesis in MTLE.

Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

The amyloid precursor protein (APP) is a widely expressed transmembrane protein that is cleaved to generate Aβ peptides in the central nervous system and is a key player in the pathogenesis of Alzheimer’s disease. The precise biological functions of APP still remain unclear although various roles have been proposed. While a commonly accepted model argues that Aβ peptides are the cause of onset and early pathogenesis of Alzheimer’s disease, recent discussions challenge this ‘Aβ hypothesis’ and suggest a direct role for APP in this neurodegenerative disease. Loss-of-function studies are an efficient way to elucidate the role of proteins and concurrently a variety of in vitro and in vivo studies has been performed for APP where protein levels have been downregulated and functional consequences monitored. Complete disruption of APP gene expression has been achieved by the generation of APP knockout animal models. Further knockdown studies using antisense and RNA interference have allowed scientists to reduce APP expression levels and have opened new avenues to explore the physiological roles of APP. In the present review, we focus on knockout and knockdown approaches that have provided insights into the physiological functions of APP and discuss their advantages and drawbacks.

BDNF and epilepsy – the bad could turn out to be good

photoreceptors were to cause a temporary black-out on each saccade, massive enough to produce an order-of-magnitude of masking, what would prevent awareness of these repeated black-outs? What masks the mask? Castet et al. do, however, reiterate an import point: the transient and incomplete attenuation of sensitivity is not sufficient to explain why the retinal motion of saccades goes unnoticed. There are clearly other mechanisms involved. One of these could be the visual masking suggested by MacKay12, and these effects might share the same mechanisms as the extra-retinal suppression signals (see Ref. 3). But more subtle processes might also be involved. In our early study7 we documented qualitative changes that occur during saccades. When a large-field moving grating was jerked abruptly backwards during saccades viewers could see the jerk (though less easily than in normal viewing) but it lacked its usual attention-grabbing salience. Thus, it appears that saccades mute the neural alarm bells that normally sound when there is a sudden, large-scale change in the visual scene. The mechanism remains to be found, but might involve damping of higher neural centres involved with visual attention.

Reticulons as Markers of Neurological Diseases: Focus on Amyotrophic Lateral Sclerosis

Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150–200 amino-acid residues. The N-terminal regions of RTNs are highly variable, and result from alternative splicing or differential promoter usage. Although widely distributed, the functions of RTNs are still poorly understood. Much interest has been focused on rtn4/nogo because of its activity as a potent inhibitor of axonal growth and repair. In the present study, we update recent knowledge on mammalian RTNs paying special attention to the involvement of these proteins as markers of neurological diseases. We also present recent data concerning RTN expression in amyotrophic lateral sclerosis, a fatal degenerative disorder characterized by loss of upper and lower motor neurons, and muscle atrophy. The rearrangement of RTN expression is regulated not only in suffering skeletal muscle but also preceding the onset of symptoms, and may relate to the disease process.

Antibody-bound β-amyloid precursor protein stimulates the production of tumor necrosis factor-α and monocyte chemoattractant protein-1 by cortical neurons

Alzheimers disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of extracellular depositions of fibrillar beta-amyloid (A beta), which is derived from the alternative processing of beta-amyloid precursor protein (APP). Although APP is thought to function as a cell surface receptor, its mode of action still remains elusive. In this study, we found that the culture medium derived from cortical neurons treated with an anti-APP antibody triggers the death of naive neurons. Biochemical and immunocytochemical analyses revealed the presence, both in the conditioned medium and in neurons, of increased levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. Furthermore, the expression of these proinflammatory mediators occurred through a c-Jun N-terminal protein kinase/c-Jun-dependent mechanism. Taken together, our findings provide evidence for a novel mechanism whereby neuronal APP in its full-length configuration induces neuronal death. Such a mechanism might be relevant to neuroinflammatory processes as those observed in AD.

HDAC‐3 Participates in the Repression of e2f‐Dependent Gene Transcription in Primary Differentiated Neurons

Abstract: Activation of e2f‐1 gene expression is an event that has been now established in many models of neuronal apoptosis. Accumulated E2F‐1 protein has also been observed in post mortem brains obtained from patients suffering from different neurodegenerative diseases. We have previously shown in primary neuronal cultures that e2f‐1 gene transcription was actively repressed in neuroprotective conditions through HDAC‐dependent regulation on the E2F‐responsive elements (E2F‐REs) located in the e2f‐1 gene promoter. Here, we further investigated the protein complex bound to these sites by gel shift analysis. We found that the specific protein binding to E2F‐REs is altered in apoptotic conditions compared to neuroprotective conditions, suggesting that the proteic constituents of the complex are likely to be modified upon apoptosis onset. Indeed, Western blot analysis showed a time‐dependent degradation of the Rb/E2F binding protein HDAC‐3 during apoptosis, a degradation that is caspase‐dependent. Altogether, these data point to HDAC‐3 as a good candidate involved in the active e2f‐1 repression necessary for neuroprotection.

Sp3 and Sp4 Transcription Factor Levels Are Increased in Brains of Patients with Alzheimer’s Disease

Background/Aims: Alzheimer’s disease (AD) is characterized by extracellular Aβ peptide deposition originating from amyloid precursor protein cleavage and intracellular neurofibrillary tangles resulting from pathological tau protein aggregation. These processes are accompanied by dramatic neuronal losses, further leading to different cognitive impairments. Neuronal death signalings involve gene expression modifications that rely on transcription factor alterations. Herein, we investigated the fate of the Sp family of transcription factors in postmortem brains from patients with AD disease and in different contexts of neuronal death. Methods/Results: By immunohistochemistry we found that the Sp3 and Sp4 levels were dramatically increased and associated with neurofibrillary tangles and pathological tau presence in neurons from the CA1 region of the hippocampus, as well as the entorhinal cortex of AD patient brains. The Sp transcription factor expression levels were further analyzed in cortical neurons in which death is induced by amyloid precursor protein signaling targeting. While the Sp1 levels remained constant, the Sp4 levels were slightly upregulated in response to the death signal. The Sp3 isoforms were rather degraded. Interestingly, when overexpressed by transfection experiments, the three Sp family members induced neuronal apoptosis, Sp3 and Sp4 being the most potent proapoptotic factors over Sp1. Conclusion: Our data evidence Sp3 and Sp4 as new hallmarks of AD in postmortem human brains and further point out that Sp proteins are potential triggers of neuronal death signaling cascades.

Brain-derived neurotrophic factor exerts opposing effects on β2-Adrenergic receptor according to depolarization status of cerebellar neurons

Abstract : To investigate the molecular mechanisms underlying brain‐derived neurotrophic factor (BDNF)‐controlled synaptic plasticity, we studied β2‐adrenergic receptor (β2‐AR) expression in cultured cerebellar granule cells. We show that, depending on the state of depolarization, BDNF exerts opposite effects on β2‐AR expression. In neurons maintained in low K+ medium (5 mM K+) that will enter apoptosis, BDNF increases β2‐AR and β2‐AR transcripts. In contrast, in depolarized neurons (high K+ medium, 25 mM K+) BDNF represses β2‐AR expression. The use of reporter genes (driven by the β2‐AR promoter or restricted regulatory elements) revealed that BDNF exerts its opposite effects at the transcriptional level by recruiting a cyclic AMP response element (CRE) and the trans‐acting factor CRE binding protein. These results provide the first evidence that a neurotrophin, e.g., BDNF, may exert an opposite effect on receptor expression and function (β2‐AR) according to the depolarization status of the neuron. Based on this finding, we propose that BDNF not only mediates neuronal survival, but is also involved in the modulation of the general sensitivity of the neuron to external signals, thus maintaining its optimal functional integration within the neuronal network.