Transmissible long-term neuroprotective and pro-cognitive effects of 1-42 beta-amyloid with A2T icelandic mutation in an Alzheimer's disease mouse model.

The amyloid cascade hypothesis assumes that the development of Alzheimer's disease (AD) is driven by a self-perpetuating cycle, in which ß-amyloid (Aß) accumulation leads to Tau pathology and neuronal damages. A particular mutation (A673T) of the amyloid precursor protein (APP) was identified among Icelandic population. It provides a protective effect against Alzheimer- and age-related cognitive decline. This APP mutation leads to the reduced production of Aß with A2T (position in peptide sequence) change (Aßice). In addition, Aßice has the capacity to form protective heterodimers in association with wild-type Aß. Despite the emerging interest in Aßice during the last decade, the impact of Aßice on events associated with the amyloid cascade has never been reported. First, the effects of Aßice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aßice protects against endogenous Aß-mediated synaptotoxicity. Second, as several studies have outlined that a single intracerebral administration of Aß can worsen Aß deposition and cognitive functions several months after the inoculation, we evaluated in vivo the long-term effects of a single inoculation of Aßice or Aß-wild-type (Aßwt) in the hippocampus of transgenic mice (APPswe/PS1dE9) over-expressing Aß1-42 peptide. Interestingly, we found that the single intra-hippocampal inoculation of Aßice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aßwt inoculation. Although Aß load was not modulated by Aßice infusion, the amount of Tau-positive neuritic plaques was significantly reduced. Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aßice-inoculated animals, which can partly explain the increased density of synapses in the Aßice animals. Thus, a single event as Aßice inoculation can improve the fate of AD-associated pathology and phenotype in mice several months after the event. These results open unexpected fields to develop innovative therapeutic strategies against AD.

Slc20a1 and Slc20a2 regulate neuronal plasticity and cognition independently of their phosphate transport ability.

In recent years, primary familial brain calcification (PFBC), a rare neurological disease characterized by a wide spectrum of cognitive disorders, has been associated to mutations in the sodium (Na)-Phosphate (Pi) co-transporter SLC20A2. However, the functional roles of the Na-Pi co-transporters in the brain remain still largely elusive. Here we show that Slc20a1 (PiT-1) and Slc20a2 (PiT-2) are the most abundant Na-Pi co-transporters expressed in the brain and are involved in the control of hippocampal-dependent learning and memory. We reveal that Slc20a1 and Slc20a2 are differentially distributed in the hippocampus and associated with independent gene clusters, suggesting that they influence cognition by different mechanisms. Accordingly, using a combination of molecular, electrophysiological and behavioral analyses, we show that while PiT-2 favors hippocampal neuronal branching and survival, PiT-1 promotes synaptic plasticity. The latter relies on a likely Otoferlin-dependent regulation of synaptic vesicle trafficking, which impacts the GABAergic system. These results provide the first demonstration that Na-Pi co-transporters play key albeit distinct roles in the hippocampus pertaining to the control of neuronal plasticity and cognition. These findings could provide the foundation for the development of novel effective therapies for PFBC and cognitive disorders.

Treating early postnatal circuit defect delays Huntington's disease onset and pathology in mice.

Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington's disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.

Alix is required for activity-dependent bulk endocytosis at brain synapses.

In chemical synapses undergoing high frequency stimulation, vesicle components can be retrieved from the plasma membrane via a clathrin-independent process called activity-dependent bulk endocytosis (ADBE). Alix (ALG-2-interacting protein X/PDCD6IP) is an adaptor protein binding to ESCRT and endophilin-A proteins which is required for clathrin-independent endocytosis in fibroblasts. Alix is expressed in neurons and concentrates at synapses during epileptic seizures. Here, we used cultured neurons to show that Alix is recruited to presynapses where it interacts with and concentrates endophilin-A during conditions triggering ADBE. Using Alix knockout (ko) neurons, we showed that this recruitment, which requires interaction with the calcium-binding protein ALG-2, is necessary for ADBE. We also found that presynaptic compartments of Alix ko hippocampi display subtle morphological defects compatible with flawed synaptic activity and plasticity detected electrophysiologically. Furthermore, mice lacking Alix in the forebrain undergo less seizures during kainate-induced status epilepticus and reduced propagation of the epileptiform activity. These results thus show that impairment of ADBE due to the lack of neuronal Alix leads to abnormal synaptic recovery during physiological or pathological repeated stimulations.

Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease.

Microtubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions that go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase (TTL). Here we show that TTL heterozygous mice exhibit decreased tyrosinated microtubules, reduced dendritic spine density and both synaptic plasticity and memory deficits. We further report decreased TTL expression in sporadic and familial Alzheimer's disease, and reduced microtubule dynamics in human neurons harbouring the familial APP-V717I mutation. Finally, we show that synapses visited by dynamic microtubules are more resistant to oligomeric amyloid-ß peptide toxicity and that expression of TTL, by restoring microtubule entry into spines, suppresses the loss of synapses induced by amyloid-ß peptide. Together, our results demonstrate that a balanced tyrosination/detyrosination tubulin cycle is necessary for the maintenance of synaptic plasticity, is protective against amyloid-ß peptide-induced synaptic damage and that this balance is lost in Alzheimer's disease, providing evidence that defective tubulin retyrosination may contribute to circuit dysfunction during neurodegeneration in Alzheimer's disease.

Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia.

The search for effective treatments for neuropsychiatric disorders is ongoing, with progress being made as brain structure and neuronal function become clearer. The central roles played by microtubules (MT) and actin in synaptic transmission and plasticity suggest that the cytoskeleton and its modulators could be relevant targets for the development of new molecules to treat psychiatric diseases. In this context, LIM Kinase - which regulates both the actin and MT cytoskeleton especially in dendritic spines, the post-synaptic compartment of the synapse - might be a good target. In this study, we analyzed the consequences of blocking LIMK1 pharmacologically using Pyr1. We investigated synaptic plasticity defects and behavioral disorders in MAP6 KO mice, an animal model useful for the study of psychiatric disorders, particularly schizophrenia. Our results show that Pyr1 can modulate MT dynamics in neurons. In MAP6 KO mice, chronic LIMK inhibition by long-term treatment with Pyr1 can restore normal dendritic spine density and also improves long-term potentiation, both of which are altered in these mice. Pyr1 treatment improved synaptic plasticity, and also reduced social withdrawal and depressive/anxiety-like behavior in MAP6 KO mice. Overall, the results of this study validate the hypothesis that modulation of LIMK activity could represent a new therapeutic strategy for neuropsychiatric diseases.

Effect of Aß Oligomers on Neuronal APP Triggers a Vicious Cycle Leading to the Propagation of Synaptic Plasticity Alterations to Healthy Neurons.

Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-ß oligomers (Aßos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aßos affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Aßos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Aßos reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that Aßos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aßos. Intracellular Aßos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aßos. Furthermore, we provide evidence that following APP processing, extracellular release of Aßos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Aßos in AD, while intracellular Aßos alter synaptic function, extracellular Aßos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.SIGNIFICANCE STATEMENT Here we provide the proof that a vicious cycle between extracellular and intracellular pools of Aß oligomers (Aßos) is required for the spreading of Alzheimer's disease (AD) pathology. We showed that extracellular Aßos propagate excitatory synaptic alterations by promoting amyloid precursor protein (APP) processing. Our results also suggest that subsequent to APP cleavage two pools of Aßos are produced. One pool accumulates inside the cytosol, inducing the loss of synaptic plasticity potential. The other pool is released into the extracellular space and contributes to the propagation of the pathology from diseased to healthy neurons. Pharmacological strategies targeting the proteolytic cleavage of APP disrupt the relationship between extracellular and intracellular Aß, providing a therapeutic approach for the disease.

Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.

Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover. However, the functional significance of autophagy in regulating cognitive function and its decline during aging remains largely elusive. Here, we show that stimulating memory upregulates autophagy in the hippocampus. Using hippocampal injections of genetic and pharmacological modulators of autophagy, we find that inducing autophagy in hippocampal neurons is required to form novel memory by promoting activity-dependent structural and functional synaptic plasticity, including dendritic spine formation, neuronal facilitation, and long-term potentiation. We show that hippocampal autophagy activity is reduced during aging and that restoring its levels is sufficient to reverse age-related memory deficits. Moreover, we demonstrate that systemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner, suggesting a prominent role for autophagy to favor the communication between systemic factors and neurons in fostering cognition. Among these youthful factors, we identify osteocalcin, a bone-derived molecule, as a direct hormonal inducer of hippocampal autophagy. Our results reveal that inducing autophagy in hippocampal neurons is a necessary mechanism to enhance the integration of novel stimulations of memory and to promote the influence of systemic factors on cognitive fitness. We also demonstrate the potential therapeutic benefits of modulating autophagy in the aged brain to counteract age-related cognitive impairments.

A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines.

Emerging evidence indicates that microtubule-associated proteins (MAPs) are implicated in synaptic function; in particular, mice deficient for MAP6 exhibit striking deficits in plasticity and cognition. How MAP6 connects to plasticity mechanisms is unclear. Here, we address the possible role of this protein in dendritic spines. We find that in MAP6-deficient cortical and hippocampal neurons, maintenance of mature spines is impaired, and can be restored by expressing a stretch of the MAP6 sequence called Mc modules. Mc modules directly bind actin filaments and mediate activity-dependent stabilisation of F-actin in dendritic spines, a key event of synaptic plasticity. In vitro, Mc modules enhance actin filament nucleation and promote the formation of stable, highly ordered filament bundles. Activity-induced phosphorylation of MAP6 likely controls its transfer to the spine cytoskeleton. These results provide a molecular explanation for the role of MAP6 in cognition, enlightening the connection between cytoskeletal dysfunction, synaptic impairment and neuropsychiatric illnesses.

Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease.

The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.

Canonical Organization of Layer 1 Neuron-Led Cortical Inhibitory and Disinhibitory Interneuronal Circuits.

Interneurons play a key role in cortical function and dysfunction, yet organization of cortical interneuronal circuitry remains poorly understood. Cortical Layer 1 (L1) contains 2 general GABAergic interneuron groups, namely single bouquet cells (SBCs) and elongated neurogliaform cells (ENGCs). SBCs predominantly make unidirectional inhibitory connections (SBC→) with L2/3 interneurons, whereas ENGCs frequently form reciprocal inhibitory and electric connections (ENGC↔) with L2/3 interneurons. Here, we describe a systematic investigation of the pyramidal neuron targets of L1 neuron-led interneuronal circuits in the rat barrel cortex with simultaneous octuple whole-cell recordings and report a simple organizational scheme of the interneuronal circuits. Both SBCs→ and ENGC ↔ L2/3 interneuronal circuits connect to L2/3 and L5, but not L6, pyramidal neurons. SBC → L2/3 interneuronal circuits primarily inhibit the entire dendritic-somato-axonal axis of a few L2/3 and L5 pyramidal neurons located within the same column. In contrast, ENGC ↔ L2/3 interneuronal circuits generally inhibit the distal apical dendrite of many L2/3 and L5 pyramidal neurons across multiple columns. Finally, L1 interneuron-led circuits target distinct subcellular compartments of L2/3 and L5 pyramidal neurons in a L2/3 interneuron type-dependent manner. These results suggest that L1 neurons form canonical interneuronal circuits to control information processes in both supra- and infragranular cortical layers.

Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers.

Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates in synaptic function as part of the molecular pathway leading to amyloid-beta (Aß)-driven synaptotoxicity in the context of Alzheimer's disease. Here, we report the implication of tau in the profound functional synaptic modification associated with synaptic plasticity. By exposing murine cultured cortical neurons to a pharmacological synaptic activation, we induced translocation of endogenous tau from the dendritic to the postsynaptic compartment. We observed similar tau translocation to the postsynaptic fraction in acute hippocampal slices subjected to long-term potentiation. When we performed live confocal microscopy on cortical neurons transfected with human-tau-GFP, we visualized an activity-dependent accumulation of tau in the postsynaptic density. Coprecipitation using phalloidin revealed that tau interacts with the most predominant cytoskeletal component present, filamentous actin. Finally, when we exposed cortical cultures to 100 nm human synthetic Aß oligomers (Aßo's) for 15 min, we induced mislocalization of tau into the spines under resting conditions and abrogated subsequent activity-dependent synaptic tau translocation. These changes in synaptic tau dynamics may rely on a difference between physiological and pathological phosphorylation of tau. Together, these results suggest that intense synaptic activity drives tau to the postsynaptic density of excitatory synapses and that Aßo-driven tau translocation to the spine deserves further investigation as a key event toward synaptotoxicity in neurodegenerative diseases.

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions.

Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.

Removal of synaptic Ca²+-permeable AMPA receptors during sleep.

There is accumulating evidence that sleep contributes to memory formation and learning, but the underlying cellular mechanisms are incompletely understood. To investigate the impact of sleep on excitatory synaptic transmission, we obtained whole-cell patch-clamp recordings from layer V pyramidal neurons in acute slices of somatosensory cortex of juvenile rats (postnatal days 21-25). In animals after the dark period, philanthotoxin 74 (PhTx)-sensitive calcium-permeable AMPA receptors (CP-AMPARs) accounted for ∼25% of total EPSP size, and current-voltage (I-V) relationships of the underlying EPSCs showed inward rectification. In contrast, in similar experiments after the light period, EPSPs were PhTx insensitive with linear I-V characteristics, indicating that CP-AMPARs were less abundant. Combined EEG and EMG recordings confirmed that slow-wave sleep-associated delta wave power peaked at the onset of the more quiescent, lights-on phase of the cycle. Subsequently, we show that burst firing, a characteristic action potential discharge mode of layer V pyramidal neurons during slow-wave sleep has a dual impact on synaptic AMPA receptor composition: repetitive burst firing without synaptic stimulation eliminated CP-AMPARs by activating serine/threonine phosphatases. Additionally, repetitive burst-firing paired with EPSPs led to input-specific long-term depression (LTD), affecting Ca(2+) impermeable AMPARs via protein kinase C signaling. In agreement with two parallel mechanisms, simple bursts were ineffective after the light period but paired bursts induced robust LTD. In contrast, incremental LTD was generated by both conditioning protocols after the dark cycle. Together, our results demonstrate qualitative changes at neocortical glutamatergic synapses that can be induced by discharge patterns characteristic of non-rapid eye movement sleep.

Early, time-dependent disturbances of hippocampal synaptic transmission and plasticity after in utero immune challenge.

BACKGROUND: Maternal infection during pregnancy is a recognized risk factor for the occurrence of a broad spectrum of psychiatric and neurologic disorders, including schizophrenia, autism, and cerebral palsy. Prenatal exposure of rats to lipopolysaccharide (LPS) leads to impaired learning and psychotic-like behavior in mature offspring, together with an enduring modification of glutamatergic excitatory synaptic transmission. The question that arises is whether any alterations of excitatory transmission and plasticity occurred at early developmental stages after in utero LPS exposure. METHODS: Electrophysiological experiments were carried out on the CA1 area of hippocampal slices from prenatally LPS-exposed male offspring from 4 to 190 days old to study the developmental profiles of long-term depression (LTD) triggered by delivering 900 shocks either single- or paired-pulse (50-msec interval) at 1 Hz and the N-methyl-D-aspartate receptor (NMDAr) contribution to synaptic transmission. RESULTS: The age-dependent drop of LTD is accelerated in prenatally LPS-exposed animals, and LTD is transiently converted into a slow-onset long-term potentiation between 16 and 25 days old. This long-term potentiation depends on Group I metabotropic glutamate receptors and protein kinase A activations and is independent of NMDArs. Maternal LPS challenge also leads to a rapid developmental impairment of synaptic NMDArs. This was associated with a concomitant reduced expression of GluN1, without any detectable alteration in the developmental switch of NMDAr GluN2 subunits. CONCLUSIONS: Aberrant forms of synaptic plasticity can be detected at early developmental stages after prenatal LPS challenge concomitant with a clear hypo-functioning of the NMDAr in the hippocampus. This might result in later-occurring brain dysfunctions.

Synthesis of C5-tetrazole derivatives of 2-amino-adipic acid displaying NMDA glutamate receptor antagonism.

Five derivatives of 2-amino-adipic acid bearing a tetrazole-substituted in C5 position were synthesized. These compounds displayed selective antagonism towards N-methyl-D: -aspartate (NMDA) receptors compared with AMPA receptors, and they were devoid of any neurotoxicity. Among these five analogues, one exhibited a higher affinity for synaptic NMDA responses than the other four. Therefore, C5 tetrazole-substituted of 2-amino-adipic acid represent an interesting series of new NMDA receptor antagonists. This approach may be considered as a new strategy to develop ligands specifically targeted to synaptic or extra-synaptic NMDA receptors.

Unveiling novel forms of hippocampal synaptic plasticity with microelectrode arrays.

In this report, we elucidate by use of microelectrode arrays novel forms of long-term depression and potentiation in the hippocampus which are triggered by low frequency afferent stimulation and which rely on the activation of metabotropic glutamate receptor of the fifth subtype (mGlu5 receptor).

Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation.

Prenatal infection is a major stressful experience leading to enhanced susceptibility for mental illnesses in humans. We recently reported in rats, that oxidative stress and glutathione (GSH) shortage occurred in fetal male brain after lipopolysaccharide (LPS) to the dams and that these responses might be involved in the neurodevelopmental deficits observed in adolescent offspring. Furthermore, pretreatment with N-acetylcysteine (NAC) before LPS avoided both delayed synaptic plasticity and mnesic performance deficits. Since NAC is one of the few medications permitted in pregnant women, this study evaluated the ability of NAC to serve as a protective therapy even after the LPS challenge. Pregnant rats received a single ip injection of E. coli LPS, two days before delivery, and were given NAC in their tap water after the LPS. GSH was evaluated at the time of its expected drop in the hippocampus of male fetuses, whereas long-term potentiation (LTP) in the CA1 area of the hippocampus and spatial memory in the water-maze were recorded in 28-day-old male offspring. Post-treatment with NAC, four hours after the LPS challenge fully prevented the drop in the GSH hippocampal content. LTP, as well as spatial learning were completely protected. NAC administration at delivery also partially restored the LTP whereas post-treatment two days later was inefficient. Another set of dams were supplemented with alpha-tocopherol prior to LPS exposure, enhancing the alpha-tocopherol levels in fetal hippocampus. This treatment did not prevent the LPS-induced synaptic plasticity impairment. These results point to fetal hippocampal GSH as a major target of the detrimental effects of in utero LPS challenge. The therapeutic window of NAC extends up to birth, suggesting that this drug might be clinically useful even after an immuno-inflammatory episode.

Neurodevelopmental damage after prenatal infection: role of oxidative stress in the fetal brain.

Prenatal infection is a major risk responsible for the occurrence of psychiatric conditions in infants. Mimicking maternal infection by exposing pregnant rodents to bacterial endotoxin lipopolysaccharide (LPS) also leads to major brain disorders in the offspring. The mechanisms of LPS action remain, however, unknown. Here, we show that LPS injection during pregnancy in rats, 2 days before delivery, triggered an oxidative stress in the hippocampus of male fetuses, evidenced by a rapid rise in protein carbonylation and by decreases in alpha-tocopherol levels and in the ratio of reduced/oxidized forms of glutathione (GSH/GSSG). Neither protein carbonylation increase nor decreases in alpha-tocopherol levels and GSH/GSSG ratio were observed in female fetuses. NMDA synaptic currents and long-term potentiation in CA1, as well as spatial recognition in the water maze, were also impaired in male but not in female 28-day-old offspring. Pretreatment with the antioxidant N-acetylcysteine prevented the LPS-induced changes in the biochemical markers of oxidative stress in male fetuses, and the delayed detrimental effects in male 28-day-old offspring, completely restoring both long-term potentiation in the hippocampus and spatial recognition performance. Oxidative stress in the hippocampus of male fetuses may thus participate in the neurodevelopmental damage induced by a prenatal LPS challenge.

Developmental switch from LTD to LTP in low frequency-induced plasticity.

The stimulation of the Schaffer collateral/commissural fibers at low frequency (1 Hz) for 3-5 min can trigger a slow-onset form of low-frequency stimulation (LFS)-long-term potentiation (LTP) (LFS-LTP) in the CA1 area of the adult rat hippocampus. Here we have examined the developmental profile of this plasticity. In 9-15 day-old rats, the application of 1 Hz for 5 min induced long-term depression (LFS-LTD). In 17-21 day-old rats, 1 Hz stimulation had no effect when applied for 5 min but mediated LTD when stimulus duration was increased to 15 min. Over 25 day-old, 1 Hz stimulation mediated LFS-LTP. LFS-LTD was dependent on both N-methyl-D-aspartate (NMDA) and mGlu5 receptor activation. Antagonists of mGlu1alpha and cannabinoid type 1 receptor were ineffective to block LTD induction. LFS-LTD was not associated with a change in paired-pulse facilitation ratio, suggesting a postsynaptic locus of expression of this plasticity. Next, we examined whether LFS-LTD was related to 'chemical' LTDs obtained by the direct stimulation of mGlu5 and NMDA receptors. The saturation of LFS-LTD completely occluded NMDA- and (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG)-induced LTD. CHPG-LTD and NMDA-LTD occluded each other. In addition, we observed that NMDA-LTD was dependent on mGlu5 receptor activation in 9-12 day old rats while it was not in animals older than 15 day-old. Therefore we postulate that during LFS application, NMDA and mGlu5 receptor could interact to trigger LTD. Low-frequency-mediated synaptic plasticity is subject to a developmental switch from NMDA- and mGlu5 receptor-dependent LTD to mGlu5 receptor-dependent LTP with a transient period (17-21 day-old) during which LFS is ineffective.