Publications by authors named "Corentin Le Magueresse"

17 Publications

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Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes.

Mol Psychiatry 2021 Apr 9. Epub 2021 Apr 9.

INSERM UMR-S 1270, Paris, France.

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.
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http://dx.doi.org/10.1038/s41380-021-01081-6DOI Listing
April 2021

An Etiological Foxp2 Mutation Impairs Neuronal Gain in Layer VI Cortico-Thalamic Cells through Increased GABA/GIRK Signaling.

J Neurosci 2020 10 5;40(44):8543-8555. Epub 2020 Oct 5.

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S 1270, Paris 75005, France

A rare mutation affecting the Forkhead-box protein P2 (FOXP2) transcription factor causes a severe monogenic speech and language disorder. Mice carrying an identical point mutation to that observed in affected patients (Foxp2 mice) display motor deficits and impaired synaptic plasticity in the striatum. However, the consequences of the mutation on neuronal function, in particular in the cerebral cortex, remain little studied. Foxp2 is expressed in a subset of Layer VI cortical neurons. Here, we used Ntsr1-EGFP mice to identify Foxp2+ neurons in the mouse auditory cortex We studied the functional impact of the R552H mutation on the morphologic and functional properties of Layer VI cortical neurons from Ntsr1-EGFP; Foxp2 male and female mice. The complexity of apical, but not basal dendrites was significantly lower in Foxp2 cortico-thalamic neurons than in control Foxp2 neurons. Excitatory synaptic inputs, but not inhibitory synaptic inputs, were decreased in Foxp2 mice. In response, homeostatic mechanisms would be expected to increase neuronal gain, i.e., the conversion of a synaptic input into a firing output. However, the intrinsic excitability of Foxp2+ cortical neurons was lower in Foxp2 neurons. A-type and delayed-rectifier (DR) potassium currents, two putative transcriptional targets of Foxp2, were not affected by the mutation. In contrast, GABA/GIRK signaling, another presumed target of Foxp2, was increased in mutant neurons. Blocking GIRK channels strongly attenuated the difference in intrinsic excitability between wild-type (WT) and Foxp2 neurons. Our results reveal a novel role for Foxp2 in the control of neuronal input/output homeostasis. Mutations of the Forkhead-box protein 2 (FOXP2) gene in humans are the first known monogenic cause of a speech and language disorder. The Foxp2 mutation may directly affect neuronal development and function in neocortex, where Foxp2 is expressed. Brain imaging studies in patients with a heterozygous mutation in FOXP2 showed abnormalities in cortical language-related regions relative to the unaffected members of the same family. However, the role of Foxp2 in neocortical neurons is poorly understood. Using mice with a Foxp2 mutation equivalent to that found in patients, we studied functional modifications in auditory cortex neurons We found that mutant neurons exhibit alterations of synaptic input and GABAB/GIRK signaling, reflecting a loss of neuronal homeostasis.
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http://dx.doi.org/10.1523/JNEUROSCI.2615-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605419PMC
October 2020

Emerging Roles of Complement in Psychiatric Disorders.

Front Psychiatry 2019 21;10:573. Epub 2019 Aug 21.

INSERM UMR-S 1270, Paris, France.

The complement system consists of more than 30 proteins that have long been known to participate to the immune defence against pathogens and to the removal of damaged cells. Their role, however, extends beyond immunity and clearance of altered "self" components in the periphery. In particular, complement proteins can be induced by all cell types in the brain. Recent discoveries highlight the role of complement in normal and pathological brain development. Specifically, the complement system mediates synaptic pruning, a developmental process whereby supernumerary synapses are eliminated in the immature brain. The complement system has been implicated in pathological synapse elimination in schizophrenia, West Nile virus infection, and lupus, all of which are associated with psychiatric manifestations. Complement also contributes to synapse loss in neurodegenerative conditions. This review provides a brief overview of the well-studied role of complement molecules in immunity. The contribution of complement to embryonic and adult neurogenesis, neuronal migration, and developmental synaptic elimination in the normal brain is reviewed. We discuss the role of complement in synapse loss in psychiatric and neurological diseases and evaluate the therapeutic potential of complement-targeting drugs for brain disorders.
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http://dx.doi.org/10.3389/fpsyt.2019.00573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712161PMC
August 2019

Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms.

Mol Psychiatry 2020 06 22;25(6):1159-1174. Epub 2019 Aug 22.

INSERM, Institut du Fer à Moulin, UMR-S 1270, Sorbonne Université, Paris, France.

Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC), and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here, we focused on changes induced by chronic maternal separation during the first 2 weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first 2 postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalised it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short-term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early-life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviours.
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http://dx.doi.org/10.1038/s41380-019-0493-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244403PMC
June 2020

RIM1/2 in retinal ganglion cells are required for the refinement of ipsilateral axons and eye-specific segregation.

Sci Rep 2017 06 12;7(1):3236. Epub 2017 Jun 12.

Institut National de la Santé et de la Recherche Médicale, UMR-S 839, 75005, Paris, France.

Neural activity is crucial for the refinement of neuronal connections during development, but the contribution of synaptic release mechanisms is not known. In the mammalian retina, spontaneous neural activity controls the refinement of retinal projections to the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC) to form appropriate topographic and eye-specific maps. To evaluate the role of synaptic release, the rab-interacting molecules (RIMs), a family of active zone proteins that play a central role in calcium-triggered release, were conditionally ablated in a subset of retinal ganglion cells (RGCs). We found that this deletion is sufficient to reduce presynaptic release probability onto dLGN neurons. Furthermore, eye-specific segregation in the dLGN and topographic refinement of ipsilateral axons in the SC and the dLGN, are impaired in RIM1/2 conditional knock-out (Rim-cDKO) mice. These defects are similar to those found when retinal activity is globally disturbed. However, reduction in synaptic release had no effect on eye-specific lamination in the SC nor on the retinotopic refinement of contralateral axons in the SC. This study highlights a potential distinction between synaptic and non-synaptic roles of neuronal activity for different mapping rules operating in visual system development.
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http://dx.doi.org/10.1038/s41598-017-03361-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468276PMC
June 2017

Electrotonic Coupling in the Pituitary Supports the Hypothalamic-Pituitary-Gonadal Axis in a Sex Specific Manner.

Front Mol Neurosci 2016 18;9:65. Epub 2016 Aug 18.

Department of Clinical Neurobiology, Medical Faculty of Heidelberg, German Cancer Research Center, University of Heidelberg Heidelberg, Germany.

Gap junctions are present in many cell types throughout the animal kingdom and allow fast intercellular electrical and chemical communication between neighboring cells. Connexin-36 (Cx36), the major neuronal gap junction protein, synchronizes cellular activity in the brain, but also in other organs. Here we identify a sex-specific role for Cx36 within the hypothalamic-pituitary-gonadal (HPG) axis at the level of the anterior pituitary gland (AP). We show that Cx36 is expressed in gonadotropes of the AP sustaining their synchronous activity. Cx36 ablation affects the entire downstream HPG axis in females, but not in males. We demonstrate that Cx36-mediated coupling between gonadotropes in the AP supports gonadotropin-releasing hormone-induced secretion of luteinizing hormone. Furthermore, we provide evidence for negative feedback regulation of Cx36 expression in the AP by estradiol. We thus, conclude that hormonally-controlled plasticity of gap junction communication at the level of the AP constitutes an additional mechanism affecting female reproduction.
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http://dx.doi.org/10.3389/fnmol.2016.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988985PMC
September 2016

The transcription factor Fezf2 directs the differentiation of neural stem cells in the subventricular zone toward a cortical phenotype.

Proc Natl Acad Sci U S A 2014 Jul 7;111(29):10726-31. Epub 2014 Jul 7.

Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg (DKFZ), 69120 Heidelberg, Germany

Postnatal neurogenesis in mammals is confined to restricted brain regions, including the subventricular zone (SVZ). In rodents, the SVZ is a lifelong source of new neurons fated to migrate to the olfactory bulb (OB), where the majority become GABAergic interneurons. The plastic capacity of neonatal and adult SVZ stem/progenitor cells is still largely unknown. By overexpressing the transcription factor Fezf2, a powerful master gene specifying the phenotype of glutamatergic subcerebral projecting neurons, we investigated whether the fate of postnatally generated SVZ neurons can be altered. Following lentiviral delivery of Fezf2 in the neonatal and adult SVZ niche, we showed that ectopic Fezf2 expression is sufficient to redirect the fate of SVZ stem cells. Thus, based on in vivo and in vitro experiments, we provide evidence that numerous Fezf2-positive OB neurons expressed glutamatergic pyramidal cell molecular markers instead of developing a GABAergic identity. Overexpression of Fezf2 had no effect on transit-amplifying progenitors or neuroblasts but was restricted to neural stem cells. Fezf2-respecified neurons bore features of pyramidal cells, exhibiting a larger cell body and a more elaborate dendritic tree, compared with OB granule cells. Patch-clamp recordings further indicated that Fezf2-respecified neurons had synaptic properties and a firing pattern reminiscent of a pyramidal cell-like phenotype. Together, the results demonstrate that neonatal and adult SVZ stem cells retain neuronal fate plasticity.
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http://dx.doi.org/10.1073/pnas.1320290111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115522PMC
July 2014

GABAergic interneurons shape the functional maturation of the cortex.

Neuron 2013 Feb;77(3):388-405

Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

From early embryonic development to adulthood, GABA release participates in the construction of the mammalian cerebral cortex. The maturation of GABAergic neurotransmission is a protracted process which takes place in discrete steps and results from the dynamic interaction between developmentally directed gene expression and brain activity. During the course of development, GABAergic interneurons contribute to key aspects of the functional maturation of the cortex in different ways, from exerting a trophic role to pacing immature neural networks. In this review, we provide an overview of the maturation of GABAergic neurotransmission and discuss the role of GABAergic interneurons in cortical wiring, plasticity, and network activity during pre- and postnatal development. We also discuss psychiatric diseases that may be considered at least in part developmental disorders of the GABAergic system.
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http://dx.doi.org/10.1016/j.neuron.2013.01.011DOI Listing
February 2013

Connexin45 modulates the proliferation of transit-amplifying precursor cells in the mouse subventricular zone.

Proc Natl Acad Sci U S A 2012 Dec 19;109(49):20107-12. Epub 2012 Nov 19.

Department of Clinical Neurobiology, University Hospital and German Cancer Research Center, DKFZ, Heidelberg, 69120 Heidelberg, Germany.

Connexins have been implicated in the regulation of precursor cell migration and proliferation during embryonic development of the mammalian brain. However, their function in postnatal neurogenesis is unclear. Here we demonstrate that connexin (Cx) 45 is expressed in transit-amplifying cells and neuroblasts in the postnatal subventricular zone (SVZ) and modulated the proliferation of SVZ-derived precursor cells in vivo. Thus, overexpression of Cx45 by retroviral injections increased the proliferation of Mash-1-positive transit-amplifying precursor cells in the SVZ. Conversely, conditional deletion of Cx45 in precursor cells decreased proliferation. Finally, we established that Cx45 positively influences cell cycle reentry via ATP signaling that involves intracellular calcium stores and ERK1/2 signaling.
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http://dx.doi.org/10.1073/pnas.1217103109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523819PMC
December 2012

Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.

PLoS One 2012 4;7(6):e37318. Epub 2012 Jun 4.

Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037318PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366956PMC
October 2012

Diazepam binding inhibitor promotes progenitor proliferation in the postnatal SVZ by reducing GABA signaling.

Cell Stem Cell 2012 Jan;10(1):76-87

Department of Clinical Neurobiology at the German Cancer Research Center and the Medical Faculty of the Heidelberg University, Heidelberg 69120, Germany.

The subventricular zone (SVZ) of the lateral ventricles is the largest neurogenic niche of the postnatal brain. New SVZ-generated neurons migrate via the rostral migratory stream to the olfactory bulb (OB) where they functionally integrate into preexisting neuronal circuits. Nonsynaptic GABA signaling was previously shown to inhibit SVZ-derived neurogenesis. Here we identify the endogenous protein diazepam binding inhibitor (DBI) as a positive modulator of SVZ postnatal neurogenesis by regulating GABA activity in transit-amplifying cells. We performed DBI loss- and gain-of-function experiments in vivo at the peak of postnatal OB neuron generation in mice and demonstrate that DBI enhances proliferation by preventing SVZ progenitors to exit the cell cycle. Furthermore, we provide evidence that DBI exerts its effect on SVZ progenitors via its octadecaneuropeptide proteolytic product (ODN) by inhibiting GABA-induced currents. Together our data reveal a regulatory mechanism by which DBI counteracts the inhibitory effect of nonsynaptic GABA signaling on subventricular neuronal proliferation.
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http://dx.doi.org/10.1016/j.stem.2011.11.011DOI Listing
January 2012

Subventricular zone-derived neuroblasts use vasculature as a scaffold to migrate radially to the cortex in neonatal mice.

Cereb Cortex 2012 Oct 17;22(10):2285-96. Epub 2011 Nov 17.

Department of Clinical Neurobiology, Heidelberg University Medical Center, D-69120 Heidelberg, Germany.

Neurons continue to be generated in the subventricular zone (SVZ) throughout postnatal development and adulthood in rodents. Whereas in adults, virtually all neuroblasts migrate tangentially to the olfactory bulb via the rostral migratory stream (RMS), in neonates, a substantial fraction migrate radially through the corpus callosum (CC) to the cortex. Mechanisms of radial cortical migration have remained unknown. We investigated this by taking recourse to enhanced green fluorescent protein (EGFP)-labeled neuroblasts in the CC and deep cortical layers of neonatal mice and found that they are frequently located adjacent to vasculature. Using time-lapse 2-photon microscopy in acute brain slices, we demonstrate that EGFP-labeled neuroblasts migrate along blood vessels. Although in close proximity to blood vessels, migrating neuroblasts are separated from endothelial cells by 1-2 layers of astrocytic processes, as revealed by electron microscopal studies of retrovirally labeled postnatally born cells. We propose that 2 factors could contribute to the decline of radial migration to the cortex during postnatal development, namely the establishment of a glial sheath delineating the RMS and a gradual decrease in the density of blood vessels in the CC. Together, our data provide evidence for a new mode of radial cortical migration of SVZ-generated neurons involving vasculature and astrocytes.
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http://dx.doi.org/10.1093/cercor/bhr302DOI Listing
October 2012

"Small axonless neurons": postnatally generated neocortical interneurons with delayed functional maturation.

J Neurosci 2011 Nov;31(46):16731-47

Department of Clinical Neurobiology, Heidelberg University Medical Center, D-69120 Heidelberg, Germany.

GABAergic interneurons of the mouse cortex are generated embryonically in the ventral telencephalon. Recent evidence, however, indicated that a subset of cortical cells expressing interneuronal markers originate in the neonatal subventricular zone. This has raised interest in the functional development and incorporation of these postnatally generated cells into cortical circuits. Here we demonstrate that these cells integrate in the cortex, and that they constitute two distinct GABAergic interneuronal classes. Whereas one class reflects the tail end of embryonic interneuron genesis, the other class comprises interneurons that are exclusively generated perinatally and postnatally. The latter constitute a novel subclass of interneurons. They are preferentially located in the deeper layers of the olfactory and orbital cortices, exhibit a unique firing pattern and slow functional maturation. Based on their distinct morphology we termed them "small axonless neurons" and indeed, unlike other cortical neurons, they communicate with their neuronal partners via dendrodendritic synapses. Finally, we provide evidence that the number of small axonless neurons is enhanced by odor enrichment, a further indication that they integrate into neural circuits and participate to olfactory processing.
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http://dx.doi.org/10.1523/JNEUROSCI.4273-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633314PMC
November 2011

Presynaptic calcium stores contribute to nicotine-elicited potentiation of evoked synaptic transmission at CA3-CA1 connections in the neonatal rat hippocampus.

Hippocampus 2007 ;17(4):316-25

Unité Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur, Paris, France.

Nicotine acetylcholine (ACh) receptors (nAChRs) are ligand-gated ion channels that are widely expressed throughout the central nervous system. It is well established that presynaptic, alpha7-containing nAChRs modulate glutamate release in several brain areas, and that this modulation requires extracellular calcium. However, the intracellular mechanisms consecutive to nAChR opening are unclear. Recent studies have suggested a role for presynaptic calcium stores in the increase of neurotransmitter release following nAChR activation. Using the minimal stimulation protocol at low-probability Schaffer collateral synapses in acute hippocampal slices from neonatal rats, we show that nicotine acting on presynaptic alpha7 nAChRs persistently upregulates glutamate release. We tested the role of calcium stores in this potentiation. First, we examined the relationship between calcium stores and glutamate release. We found that bath application of SERCA pump inhibitors (cyclopiazonic acid and thapsigargin), as well as an agonist of ryanodine receptors (ryanodine 2 microM) increases the probability of glutamate release at CA3-CA1 synapses, decreases the coefficient of variation and the paired-pulse ratio, indicating that presynaptic activation of calcium-induced calcium release can modulate glutamatergic transmission. Next, we investigated whether blocking calcium release from internal stores could alter the effect of nicotine. Preincubation with thapsigargin (10 microM), cyclopiazonic acid (30 microM), or with a high (blocking) concentration of ryanodine (100 microM) for 30 min to 5 h failed to block the effect of nicotine. However, after preincubation in ryanodine, nicotine-elicited potentiation was significantly shortened. These results indicate that at immature Schaffer collateral-CA1 synapses, activation of presynaptic calcium stores is not necessary for but contributes to nicotine-elicited increase of neurotransmitter release.
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http://dx.doi.org/10.1002/hipo.20271DOI Listing
June 2007

Nicotinic modulation of network and synaptic transmission in the immature hippocampus investigated with genetically modified mice.

J Physiol 2006 Oct 10;576(Pt 2):533-46. Epub 2006 Aug 10.

Neurobiology Department, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy.

The hippocampus, a key structure in learning and memory processes, receives a powerful cholinergic innervation from the septum and contains nicotinic acetylcholine receptors (nAChRs). Early in postnatal development, activation of nAChRs by nicotine or endogenous acetylcholine contributes to enhance synaptic signalling. Here, the patch-clamp technique was used to assess the contribution of alpha7 and beta2-containing (alpha7* and beta2*) nAChRs to nicotine-elicited modulation of GABAergic and glutamatergic activity at the network and single-cell level in the immature hippocampus of wild-type (WT), alpha7-/- and beta2-/- mice. We found that alpha7* and beta2* nAChRs were sufficient to modulate nicotine-induced increase in frequency of spontaneously occurring giant depolarizing potentials (GDPs), which are generated at the network level by the synergistic action of glutamate and depolarizing GABA, and thought to play a crucial role in neuronal wiring. However, alpha7* but not beta2* receptors were essential in nicotine-induced increase of interictal discharge frequency recorded after postnatal day 3 in the presence of bicuculline, when GABA shifted from the depolarizing to the hyperpolarizing direction. To correlate these observations with nicotine-elicited changes in synaptic transmission, we recorded spontaneous GABAergic and glutamatergic postsynaptic currents in pyramidal cells and interneurons localized in stratum oriens, stratum pyramidale and stratum radiatum, in slices obtained from WT and knock-out animals. We found that early in postnatal life alpha7* and beta2* nAChRs exert a fine regional modulation of GABAergic and glutamatergic transmission that underlies nicotine-elicited changes in network synchronization.
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http://dx.doi.org/10.1113/jphysiol.2006.117572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890366PMC
October 2006

Persistent decrease in synaptic efficacy induced by nicotine at Schaffer collateral-CA1 synapses in the immature rat hippocampus.

J Physiol 2004 Sep 22;559(Pt 3):863-74. Epub 2004 Jul 22.

Neuroscience Programme, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed within the brain where they contribute to the regulation of higher cognitive functions. The loss of the cholinergic function in Alzheimer's disease patients, along with the well-known memory enhancing effect of nicotine, emphasizes the role of cholinergic signalling in memory functions. The hippocampus, a key structure in learning and memory, is endowed with nAChRs localized at pre- and postsynaptic levels. In previous work on the immature hippocampus we have shown that, at low probability (P) synapses, activation of alpha7 nAChRs by nicotine or by endogenously released acetylcholine persistently enhanced glutamate release and converted 'presynaptically silent' synapses into functional ones. Here we show that in the same preparation, at high P synapses, nicotine induces long-term depression of AMPA- and NMDA-mediated synaptic currents. This effect was mediated by presynaptic alpha7- and beta2-containing receptors and was associated with an increase in the paired pulse ratio and in the coefficient of variation. High P synapses could be converted into low P and vice versa by changing the extracellular Ca2+/Mg2+ ratio. In these conditions nicotine was able to persistently potentiate or depress synaptic responses depending on the initial P-values. A bi-directional control of synaptic plasticity by nicotine would considerably enhance the computational properties of the network during a critical period of postnatal development thus contributing to sculpt the neuronal circuit.
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http://dx.doi.org/10.1113/jphysiol.2004.067041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665176PMC
September 2004

Nicotine activates immature "silent" connections in the developing hippocampus.

Proc Natl Acad Sci U S A 2003 Feb 11;100(4):2059-64. Epub 2003 Feb 11.

Neuroscience Program and Istituto Nazionale di Fisica della Materia Unit, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy.

In the hippocampus at birth, most glutamatergic synapses are immature and functionally "silent" either because the neurotransmitter is released in insufficient amount to activate low-affinity alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors or because the appropriate receptor system is missing or nonfunctional. Here we show that, in the newborn rat, a brief application of nicotine at immature Schaffer collateral-CA1 connections strongly enhances neurotransmitter release and converts presynaptically silent synapses into conductive ones. This effect is persistent and can be mimicked by endogenous acetylcholine released from cholinergic fibers. Thus, during a critical period of postnatal development, activation of nicotinic acetylcholine receptors contributes to the maturation of functional synaptic contacts and the wiring of adult hippocampal circuitry.
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http://dx.doi.org/10.1073/pnas.0437947100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC149958PMC
February 2003