Sandra Santos

Role of the brain‐derived neurotrophic factor at glutamatergic synapses

The neurotrophin brain‐derived neurotrophic factor (BDNF) plays an important role in the activity‐dependent regulation of synaptic structure and function, particularly of the glutamatergic synapses. BDNF may be released in the mature form, which activates preferentially TrkB receptors, or as proBDNF, which is coupled to the stimulation of the p75NTR. In the mature form BDNF induces rapid effects on glutamate release, and may induce short‐ and long‐term effects on the postsynaptic response to the neurotransmitter. BDNF may affect glutamate receptor activity by inducing the phosphorylation of the receptor subunits, which may also affect the interaction with intracellular proteins and, consequently, their recycling and localization to defined postsynaptic sites. Stimulation of the local protein synthesis and transcription activity account for the delayed effects of BDNF on glutamatergic synaptic strength. Several evidences show impaired synaptic plasticity of glutamatergic synapses in diseases where compromised BDNF function has been observed, such as Huntingtons disease, depression, anxiety, and the BDNF polymorphism Val66Met, suggesting that upregulating BDNF‐activated pathways may be therapeutically relevant. This review focuses on recent advances in the understanding of the regulation of the glutamatergic synapse by BDNF, and its implications in synaptic plasticity.

Regulation of AMPA receptors and synaptic plasticity.

Neuronal activity controls the strength of excitatory synapses by mechanisms that include changes in the postsynaptic responses mediated by AMPA receptors. These receptors account for most fast responses at excitatory synapses of the CNS, and their activity is regulated by various signaling pathways which control the electrophysiological properties of AMPA receptors and their interaction with numerous intracellular regulatory proteins. AMPA receptor phosphorylation/dephosphorylation and interaction with other proteins control their recycling and localization to defined postsynaptic sites, thereby regulating the strength of the synapse. This review focuses on recent advances in the understanding of the molecular mechanisms of regulation of AMPA receptors, and the implications in synaptic plasticity.

Leptin regulates AMPA receptor trafficking via PTEN inhibition

The hormone leptin can cross the blood–brain barrier and influences numerous brain functions (Harvey, 2007). Indeed, recent studies have demonstrated that leptin regulates activity-dependent synaptic plasticity in the CA1 region of the hippocampus (Shanley et al., 2001; Li et al., 2002; Durakoglugil et al., 2005; Moult et al., 2009). It is well documented that trafficking of AMPA receptors is pivotal for hippocampal synaptic plasticity (Collingridge et al., 2004), but there is limited knowledge of how hormonal systems like leptin influence this process. In this study we have examined how leptin influences AMPA receptor trafficking and in turn how this impacts on excitatory synaptic function. Here we show that leptin preferentially increases the cell surface expression of GluR1 and the synaptic density of GluR2-lacking AMPA receptors in adult hippocampal slices. The leptin-induced increase in surface GluR1 required NMDA receptor activation and was associated with an increase in cytoplasmic PtdIns(3,4,5)P3 levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5)P3 levels. Moreover, inhibition of PTEN mimicked and occluded the effects of leptin on GluR1 trafficking and excitatory synaptic strength. These data indicate that leptin, via a novel pathway involving PTEN inhibition, promotes GluR1 trafficking to hippocampal synapses. This process has important implications for the role of leptin in hippocampal synaptic function in health and disease.

Neuroprotective properties ofValeriana officinalis extracts

Valeriana officinalis have been used in traditional medicine for its sedative, hypnotic, and anticonvulsant effects. There are several eports in the literature supporting a GABAergic mechanism of action for valerian. The rationale of the present work is based on the concept that by decreasing neuronal network excitability valerian consumption may contribute to neuroprotection. The aim of our investigation was to evaluate the neuroprotective effects ofV. officinalis against the toxicity induced by amyloid beta peptide 25–35 [Aβ(25–35)]. Cultured rat hip-pocampal neurons were exposed to Aβ(25–35)(25 μM) for 24–48 h,after which morphological and biochemical properties were evaluated. The neuronal injury evoked by Aβ, which includes a decrease in cell educing capacity and associated neuronal degeneration, was prevented by valerian extract. Analysis of intracellular free calcium ([Ca2+]i)indicated that the neuroprotective mechanisms may involve the inhibition of excess influx of Ca2+ following neuronal injury. Moreover, membrane peroxidation in rat hippocampal synaptosomes was evaluated, and our data indicate that valerian extract partially inhibited ascorbate/iron-induced peroxidation.In conclusion we show evidence that the signalling pathways involving [Ca2+]i and the redox state of the cells may play a central ole in the neuroprotective properties ofV. officinalis extract against Aβ toxicity. The novelty of the findings of the present work, indicating neuroprotective properties of valerian against Aβ toxicity may, at the long-term, contribute to introduction of a new elevant use of valerian alcoholic extract to prevent neuronal degeneration in aging or neurodegenerative disorders.

Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

Significance Ghrelin is a peptide released from the empty stomach into circulation, and which acts on the brain to promote appetite. Recent studies showed that ghrelin also affects cognition, but the mechanism for this effect is unknown. We show that activation of ghrelin receptors in the hippocampus enhances synaptic signaling by glutamate, the major excitatory neurotransmitter in the brain. Ghrelin promotes the synaptic accumulation of glutamate receptors of the AMPA subtype, and increases long-term potentiation, one form of synaptic plasticity that is thought to underlie learning and memory. These molecular effects of ghrelin in the hippocampus may contribute to the cognition-enhancing role of ghrelin. Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning.

Regulation of synapse composition by protein acetylation: the role of acetylated cortactin

Summary Protein acetylation affects synaptic plasticity and memory, but its effects on synapse composition have not been addressed. We found that protein acetylation promotes the dendritic clustering of the excitatory postsynaptic scaffold protein PSD95 in hippocampal neurons, without affecting the total levels of this protein. Cortactin, an F-actin-binding protein enriched in dendritic spines, is a substrate for acetylation and has a role in spine morphogenesis. Recent studies showed that cortactin acetylation changes its ability to bind F-actin and regulates cellular motility, but the function of cortactin acetylation in neuronal cells is so far unknown. We tested whether acetylation of cortactin influences its morphogenic function by overexpressing wild-type cortactin, or the mimetic mutants for acetylated or deacetylated cortactin, in hippocampal neurons, and found that cortactin acetylation has an impact on PSD95 clustering, independent from its function as actin dynamics regulator. Moreover, acetylated cortactin can rescue the reduction in PSD95 clustering mediated by knockdown of cortactin. We also found that acetylation of cortactin is correlated with decreased cortactin interaction with p140Cap and Shank1, and with lower cortactin phosphorylation at tyrosine 421. The neurotrophin BDNF promoted the acetylation of cortactin in hippocampal neurons, suggesting that BDNF may regulate excitatory synapses and PSD95 dendritic clustering at least in part by changing the acetylation level of cortactin. Our findings unravel an unsuspected role for cortactin acetylation in the regulation of PSD95 dendritic clustering, which may work in concert with cortactins role in spine development.

Contactin-associated Protein 1 (Caspr1) Regulates the Traffic and Synaptic Content of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)-type Glutamate Receptors

Background: The strength of excitatory synapses is determined by the synaptic content of AMPA receptors. Results: We found that Contactin associated protein 1 (Caspr1) binds to AMPA receptors and regulates their neuronal cell surface and synaptic expression. Conclusion: Caspr1 is a binding partner for AMPA receptors, which regulates their traffic and synaptic targeting. Significance: Caspr1 is a new player in plasticity mechanisms in excitatory synapses. Glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type mediate fast excitatory synaptic transmission in the CNS. Synaptic strength is modulated by AMPA receptor binding partners, which regulate receptor synaptic targeting and functional properties. We identify Contactin-associated protein 1 (Caspr1) as an AMPA receptor interactor. Caspr1 is present in synapses and interacts with AMPA receptors in brain synaptic fractions. Coexpression of Caspr1 with GluA1 increases the amplitude of glutamate-evoked currents. Caspr1 overexpression in hippocampal neurons increases the number and size of synaptic GluA1 clusters, whereas knockdown of Caspr1 decreases the intensity of synaptic GluA1 clusters. Hence, Caspr1 is a regulator of the trafficking of AMPA receptors to synapses.

A single exposure to morphine induces long-lasting hyporeactivity of rat caudate putamen dopaminergic nerve terminals.

Abstract: The long‐lasting effects of exposure to drugs of abuse on the brain is a central theme in drug addiction research. This study was designed to evaluate whether enduring neurochemical adaptations within caudate putamen can be evoked by a single injection of a high dose of morphine. Rats were pretreated once with 10 mg/kg morphine. Seven days later the effect of another injection of 10 mg/kg morphine on total levels of dopamine (DA), 3,4‐dihydroxyphenylacetic acid (DOPAC), and homovanilic acid (HVA) in caudate putamen was assessed in half the pretreated animals. An irreversible μ‐opioid receptor antagonist, cloccinamox (C‐CAM; 0.1 mg/kg), significantly antagonized the elevation of the HVA/DA ratio, but not the elevation of the DOPAC/DA ratio induced by morphine in the caudate putamen from drug‐naive animals. Pretreatment with morphine blunted changes in the HVA/DA ratio induced by another morphine challenge, but it had no effect on the DOPAC/DA ratio within the caudate putamen. Therefore, a single dose of 10 mg/kg morphine hampered nigrostriatal DA release and extraneuronal metabolism, μ‐opioid receptor mediated, on another 10 mg/kg morphine challenge. This confirms that the first exposure to morphine does not go without long‐lasting neurochemical adaptations.