It is well accepted that populations of neurons responsible for the onset and maintenance of para... more It is well accepted that populations of neurons responsible for the onset and maintenance of paradoxical sleep (PS) are restricted to the brainstem. To localize the structures involved and to reexamine the role of mesopontine cholinergic neurons, we compared the distribution of Fos- and choline acetyltransferase-labelled neurons in the brainstem of control rats, rats selectively deprived of PS for ≈ 72 h and rats allowed to recover from such deprivation. Only a few cholinergic neurons from the laterodorsal (LDTg) and pedunculopontine tegmental nuclei were Fos-labelled after PS recovery. In contrast, a large number of noncholinergic Fos-labelled cells positively correlated with the percentage of time spent in PS was observed in the LDTg, sublaterodorsal, alpha and ventral gigantocellular reticular nuclei, structures known to contain neurons specifically active during PS. In addition, a large number of Fos-labelled cells were seen after PS rebound in the lateral, ventrolateral and dorsal periaqueductal grey, dorsal and lateral paragigantocellular reticular nuclei and the nucleus raphe obscurus. Interestingly, half of the cells in the latter nucleus were immunoreactive to choline acetyltransferase. In contrast to the well-accepted hypothesis, our results strongly suggest that neurons active during PS, recorded in the mesopontine cholinergic nuclei, are in the great majority noncholinergic. Our findings further demonstrate that many brainstem structures not previously identified as containing neurons active during PS contain cholinergic or noncholinergic neurons active during PS, and these structures may therefore play a key role during this state. Altogether, our results open a new avenue of research to identify the specific role of the populations of neurons revealed, their interrelations and their neurochemical identity.
In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase... more In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase paradoxically characterized by cortical activation and rapid eye movements and a muscle atonia. Soon after, he showed that it was still present in ''pontine cats'' in which all structures rostral to the brainstem have been removed. Later on, it was demonstrated that the pontine peri-locus coeruleus a (peri-LCa in cats, corresponding to the sublaterodorsal nucleus, SLD, in rats) is responsible for PS onset. It was then proposed that the onset and maintenance of PS is due to a reciprocal inhibitory interaction between neurons presumably cholinergic specifically active during PS localized in this region and monoaminergic neurons. In the last decade, we have tested this hypothesis with our model of head-restrained rats and functional neuroanatomical studies. Our results confirmed that the SLD in rats contains the neurons responsible for the onset and maintenance of PS. They further indicate that (1) these neurons are non-cholinergic possibly glutamatergic neurons, (2) they directly project to the glycinergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus (GiV), (3) the main neurotransmitter responsible for their inhibition during waking (W) and slow wave sleep (SWS) is GABA rather than monoamines, (4) they are constantly and tonically excited by glutamate and (5) the GABAergic neurons responsible for their tonic inhibition during W and SWS are localized in the deep mesencephalic reticular nucleus (DPMe). We also showed that the tonic inhibition of locus coeruleus (LC) noradrenergic and dorsal raphe (DRN) serotonergic neurons during sleep is due to a tonic GABAergic inhibition by neurons localized in the dorsal paragigantocellular reticular nucleus (DPGi) and the ventrolateral periaqueductal gray (vlPAG). We propose that these GABAergic neurons also inhibit the GAB-Aergic neurons of the DPMe at the onset and during PS and are therefore responsible for the onset and maintenance of PS.
Background: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocr... more Background: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation.
Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzhei... more Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer's disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer's disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABAA receptor antag...
The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are bel... more The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and postnatal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired longterm but not short-term memory in both, spatial and nonspatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus.
Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological diso... more Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.
Levels of educational and occupational attainment, as components of cognitive reserve, may modify... more Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice-before amyloidogenesis has started-reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging.
Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mecha... more Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuronspecific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.
Proceedings of the National Academy of Sciences of the United States of America, Jan 16, 2012
In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, hal... more In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by elect...
Background: According to the 'amyloidogenic hypothesis', brain accumulation of amyloid-beta (Abet... more Background: According to the 'amyloidogenic hypothesis', brain accumulation of amyloid-beta (Abeta) peptide species, which ultimately deposits into amyloid plaques, would be central and causative of the neuronal degeneration and cognitive decline observed in patients affected by Alzheimer's disease (AD). Interestingly, pre-fibrillar (i.e. pre-plaque), low-n oligomers (dimers, trimers) of Abeta have been found to inhibit long-term potentiation in normal rodent hippocampus as well as interfere with the retrieval of established memories. On the other hand, the highly insoluble pyroglutamate-Abeta (pE-Abeta), which results from N-terminal cleavage and subsequent enzymatic transformation of an exposed glutamate residue, is highly abundant in the brains of AD patients, and some recent studies suggest a correlation to their pathological stage. Methods: 13 month old McGill-R-Thy1-APP rats where behaviorally characterized by means of the Morris water maze and amyloid peptide accumulation in their brain investigated by immunohistochemistry and ELISA using Abeta species-specific antibodies. Results: Interestingly, the accumulation of the highly toxic Abeta1-42 over Abeta1-40 species measured in soluble brain extracts was found particularly abundant in homozygous rats as compared to hemizygous littermates (10-fold higher), positively correlating with their cognitive decline. On the other hand, comparable amounts of the two amyloid species were measured in the CSF of those animals, thus replicating what observed in human patients. Specific pE-Abeta immunoreactivity was found within amyloid plaques deposited in the brain of homozygous animals. A further investigation by ELISA confirmed a specific accumulation of the peptide within TBS-insoluble protein fractions from homozygous rats, whereas no signal was detectable from hemizygous or wt littermates. Conclusions: If on the one hand soluble (i.e. oligomeric) Abeta inversely correlates with the cog-nitive status of McGill-R-Thy1 tg rats, the highly insoluble pE-Abeta specifically accumulates in the brain of homozygous animals, where signs of an extended plaque pathology are detectable. Identifying the contribution of each of these two aspects to the amyloid pathology progression and the cognitive decline associated with AD will provide a better understanding for the development of new therapeutic strategies.
controls. We ran association tests separately for brain and blood DNA samples, using logistic reg... more controls. We ran association tests separately for brain and blood DNA samples, using logistic regression controlling for age the number of ApoE4 alleles. 5131 genomic regions for blood and 4945 genomic regions for brain samples were tested for association. No region of significance (5e-6) for genome-wide association tests was found in blood samples while 36 regions >5KB were found in brain samples. CNV frequencies range from infrequent (10%) to rare (<2%) in these regions with high OR. Conclusions: CNV analysis suggests rare CNVs with strong effect size on the risk of Alzheimer's disease. We are currently validating our findings using an additional ADGC dataset of 2256 subjects genotyped using Illumina OmniExpress array. Findings will be presented at the ICAD conference.
Amyloid- peptide species accumulating in the brain of patients with Alzheimer's disease are assu... more Amyloid- peptide species accumulating in the brain of patients with Alzheimer's disease are assumed to have a neurotoxic action and hence to be key actors in the physiopathology of this neurodegenerative disease. We have studied a new mouse mutant (APPxPS1-Ki) line developing both early-onset brain amyloid- deposition and, in contrast to most of transgenic models, subsequent neuronal loss. In 6-monthold mice, we observed cell layer atrophies in the hippocampus, together with a dramatic decrease in neurogenesis and a reduced brain blood perfusion as measured in vivo by magnetic resonance imaging. In these mice, neurological impairments and spatial hippocampal dependant memory deficits were also substantiated and worsened with aging. We described here a phenotype of APPxPS1-Ki mice that summarizes several neuroanatomical alterations and functional deficits evocative of the human pathology. Such a transgenic model that displays strong face validity might be highly beneficial to future research on AD physiopathogeny and therapeutics.
The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzh... more The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-b (Ab) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Ab overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex. Soluble Ab was observed in the dentate gyrus, and Ab deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Ab expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models and human patients with AD.
New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. T... more New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functions. (C. Rampon). Abbreviations: BrdU, 5-bromo-2'deoxyuridine; DG, dentate gyrus; MAM, methylazoxymethanol acetate; NeuN, neuron-specific nuclear protein.
Animal models of genetic diseases obtained by transferring human mutated genes in the mouse are w... more Animal models of genetic diseases obtained by transferring human mutated genes in the mouse are widely used in biomedical based research. They constitute efficient tools to study mechanisms underlying abnormal phenotypes. Unfortunately, the phenotype of the transgene is often obscured by the genetic background of the embryonic stem cells and that of the recipient strain used to create the transgenic line. It is also known, from the literature, that repeatedly backcrossing a transgenic strain to an inbred background may have unfavorable effects that can result in the loss of the transgenic line. In order to analyze the influences of the genetic background on the transgene expression, we studied the effects of the hAPPswe transgene involved in Alzheimer's Amyloid Pathology, in 3 genetic backgrounds differing by their genetic heterogeneity (homozygous vs heterozygous) and the strain of origin (C57BL6, CBA, B6SJL F1) after only one generation backcrossing. Three different behavioral paradigms were used to assess the psychological and cognitive phenotypic differences: elevated plus maze, morris navigation task and contextual fear conditioning. Our data indicate that the best solution to maintain the transgenic line is to backcross repeatedly the transgenic mice into the F1 hybrid cross that was used to create the transgenic strain, whereas phenotyping should be performed comparatively after only one generation backcrossing into various well chosen F1 or inbred backgrounds.
It is now widely accepted that new neurons continue to be added to the brain throughout life incl... more It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging. Although it is not yet clear whether neurogenesis leads to the production of fully functional mature neurons in AD brains, these findings open prospects for cell-replacement therapies. Strategies aimed at promoting neurogenesis may also contribute to improve cognitive deficits caused by normal or pathological aging.
Our data indicate that overproduction of A and the consequent appearance of amyloid plaques caus... more Our data indicate that overproduction of A and the consequent appearance of amyloid plaques cause an overall reduction in the number of adult-generated hippocampal neurons. Diminished capacity for hippocampal neuron replacement may contribute to the cognitive decline observed in these mice.
It is well accepted that populations of neurons responsible for the onset and maintenance of para... more It is well accepted that populations of neurons responsible for the onset and maintenance of paradoxical sleep (PS) are restricted to the brainstem. To localize the structures involved and to reexamine the role of mesopontine cholinergic neurons, we compared the distribution of Fos- and choline acetyltransferase-labelled neurons in the brainstem of control rats, rats selectively deprived of PS for ≈ 72 h and rats allowed to recover from such deprivation. Only a few cholinergic neurons from the laterodorsal (LDTg) and pedunculopontine tegmental nuclei were Fos-labelled after PS recovery. In contrast, a large number of noncholinergic Fos-labelled cells positively correlated with the percentage of time spent in PS was observed in the LDTg, sublaterodorsal, alpha and ventral gigantocellular reticular nuclei, structures known to contain neurons specifically active during PS. In addition, a large number of Fos-labelled cells were seen after PS rebound in the lateral, ventrolateral and dorsal periaqueductal grey, dorsal and lateral paragigantocellular reticular nuclei and the nucleus raphe obscurus. Interestingly, half of the cells in the latter nucleus were immunoreactive to choline acetyltransferase. In contrast to the well-accepted hypothesis, our results strongly suggest that neurons active during PS, recorded in the mesopontine cholinergic nuclei, are in the great majority noncholinergic. Our findings further demonstrate that many brainstem structures not previously identified as containing neurons active during PS contain cholinergic or noncholinergic neurons active during PS, and these structures may therefore play a key role during this state. Altogether, our results open a new avenue of research to identify the specific role of the populations of neurons revealed, their interrelations and their neurochemical identity.
In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase... more In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase paradoxically characterized by cortical activation and rapid eye movements and a muscle atonia. Soon after, he showed that it was still present in ''pontine cats'' in which all structures rostral to the brainstem have been removed. Later on, it was demonstrated that the pontine peri-locus coeruleus a (peri-LCa in cats, corresponding to the sublaterodorsal nucleus, SLD, in rats) is responsible for PS onset. It was then proposed that the onset and maintenance of PS is due to a reciprocal inhibitory interaction between neurons presumably cholinergic specifically active during PS localized in this region and monoaminergic neurons. In the last decade, we have tested this hypothesis with our model of head-restrained rats and functional neuroanatomical studies. Our results confirmed that the SLD in rats contains the neurons responsible for the onset and maintenance of PS. They further indicate that (1) these neurons are non-cholinergic possibly glutamatergic neurons, (2) they directly project to the glycinergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus (GiV), (3) the main neurotransmitter responsible for their inhibition during waking (W) and slow wave sleep (SWS) is GABA rather than monoamines, (4) they are constantly and tonically excited by glutamate and (5) the GABAergic neurons responsible for their tonic inhibition during W and SWS are localized in the deep mesencephalic reticular nucleus (DPMe). We also showed that the tonic inhibition of locus coeruleus (LC) noradrenergic and dorsal raphe (DRN) serotonergic neurons during sleep is due to a tonic GABAergic inhibition by neurons localized in the dorsal paragigantocellular reticular nucleus (DPGi) and the ventrolateral periaqueductal gray (vlPAG). We propose that these GABAergic neurons also inhibit the GAB-Aergic neurons of the DPMe at the onset and during PS and are therefore responsible for the onset and maintenance of PS.
Background: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocr... more Background: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation.
Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzhei... more Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer's disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer's disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABAA receptor antag...
The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are bel... more The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and postnatal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired longterm but not short-term memory in both, spatial and nonspatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus.
Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological diso... more Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.
Levels of educational and occupational attainment, as components of cognitive reserve, may modify... more Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice-before amyloidogenesis has started-reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging.
Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mecha... more Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuronspecific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.
Proceedings of the National Academy of Sciences of the United States of America, Jan 16, 2012
In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, hal... more In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by elect...
Background: According to the 'amyloidogenic hypothesis', brain accumulation of amyloid-beta (Abet... more Background: According to the 'amyloidogenic hypothesis', brain accumulation of amyloid-beta (Abeta) peptide species, which ultimately deposits into amyloid plaques, would be central and causative of the neuronal degeneration and cognitive decline observed in patients affected by Alzheimer's disease (AD). Interestingly, pre-fibrillar (i.e. pre-plaque), low-n oligomers (dimers, trimers) of Abeta have been found to inhibit long-term potentiation in normal rodent hippocampus as well as interfere with the retrieval of established memories. On the other hand, the highly insoluble pyroglutamate-Abeta (pE-Abeta), which results from N-terminal cleavage and subsequent enzymatic transformation of an exposed glutamate residue, is highly abundant in the brains of AD patients, and some recent studies suggest a correlation to their pathological stage. Methods: 13 month old McGill-R-Thy1-APP rats where behaviorally characterized by means of the Morris water maze and amyloid peptide accumulation in their brain investigated by immunohistochemistry and ELISA using Abeta species-specific antibodies. Results: Interestingly, the accumulation of the highly toxic Abeta1-42 over Abeta1-40 species measured in soluble brain extracts was found particularly abundant in homozygous rats as compared to hemizygous littermates (10-fold higher), positively correlating with their cognitive decline. On the other hand, comparable amounts of the two amyloid species were measured in the CSF of those animals, thus replicating what observed in human patients. Specific pE-Abeta immunoreactivity was found within amyloid plaques deposited in the brain of homozygous animals. A further investigation by ELISA confirmed a specific accumulation of the peptide within TBS-insoluble protein fractions from homozygous rats, whereas no signal was detectable from hemizygous or wt littermates. Conclusions: If on the one hand soluble (i.e. oligomeric) Abeta inversely correlates with the cog-nitive status of McGill-R-Thy1 tg rats, the highly insoluble pE-Abeta specifically accumulates in the brain of homozygous animals, where signs of an extended plaque pathology are detectable. Identifying the contribution of each of these two aspects to the amyloid pathology progression and the cognitive decline associated with AD will provide a better understanding for the development of new therapeutic strategies.
controls. We ran association tests separately for brain and blood DNA samples, using logistic reg... more controls. We ran association tests separately for brain and blood DNA samples, using logistic regression controlling for age the number of ApoE4 alleles. 5131 genomic regions for blood and 4945 genomic regions for brain samples were tested for association. No region of significance (5e-6) for genome-wide association tests was found in blood samples while 36 regions >5KB were found in brain samples. CNV frequencies range from infrequent (10%) to rare (<2%) in these regions with high OR. Conclusions: CNV analysis suggests rare CNVs with strong effect size on the risk of Alzheimer's disease. We are currently validating our findings using an additional ADGC dataset of 2256 subjects genotyped using Illumina OmniExpress array. Findings will be presented at the ICAD conference.
Amyloid- peptide species accumulating in the brain of patients with Alzheimer's disease are assu... more Amyloid- peptide species accumulating in the brain of patients with Alzheimer's disease are assumed to have a neurotoxic action and hence to be key actors in the physiopathology of this neurodegenerative disease. We have studied a new mouse mutant (APPxPS1-Ki) line developing both early-onset brain amyloid- deposition and, in contrast to most of transgenic models, subsequent neuronal loss. In 6-monthold mice, we observed cell layer atrophies in the hippocampus, together with a dramatic decrease in neurogenesis and a reduced brain blood perfusion as measured in vivo by magnetic resonance imaging. In these mice, neurological impairments and spatial hippocampal dependant memory deficits were also substantiated and worsened with aging. We described here a phenotype of APPxPS1-Ki mice that summarizes several neuroanatomical alterations and functional deficits evocative of the human pathology. Such a transgenic model that displays strong face validity might be highly beneficial to future research on AD physiopathogeny and therapeutics.
The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzh... more The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-b (Ab) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Ab overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex. Soluble Ab was observed in the dentate gyrus, and Ab deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Ab expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models and human patients with AD.
New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. T... more New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functions. (C. Rampon). Abbreviations: BrdU, 5-bromo-2'deoxyuridine; DG, dentate gyrus; MAM, methylazoxymethanol acetate; NeuN, neuron-specific nuclear protein.
Animal models of genetic diseases obtained by transferring human mutated genes in the mouse are w... more Animal models of genetic diseases obtained by transferring human mutated genes in the mouse are widely used in biomedical based research. They constitute efficient tools to study mechanisms underlying abnormal phenotypes. Unfortunately, the phenotype of the transgene is often obscured by the genetic background of the embryonic stem cells and that of the recipient strain used to create the transgenic line. It is also known, from the literature, that repeatedly backcrossing a transgenic strain to an inbred background may have unfavorable effects that can result in the loss of the transgenic line. In order to analyze the influences of the genetic background on the transgene expression, we studied the effects of the hAPPswe transgene involved in Alzheimer's Amyloid Pathology, in 3 genetic backgrounds differing by their genetic heterogeneity (homozygous vs heterozygous) and the strain of origin (C57BL6, CBA, B6SJL F1) after only one generation backcrossing. Three different behavioral paradigms were used to assess the psychological and cognitive phenotypic differences: elevated plus maze, morris navigation task and contextual fear conditioning. Our data indicate that the best solution to maintain the transgenic line is to backcross repeatedly the transgenic mice into the F1 hybrid cross that was used to create the transgenic strain, whereas phenotyping should be performed comparatively after only one generation backcrossing into various well chosen F1 or inbred backgrounds.
It is now widely accepted that new neurons continue to be added to the brain throughout life incl... more It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging. Although it is not yet clear whether neurogenesis leads to the production of fully functional mature neurons in AD brains, these findings open prospects for cell-replacement therapies. Strategies aimed at promoting neurogenesis may also contribute to improve cognitive deficits caused by normal or pathological aging.
Our data indicate that overproduction of A and the consequent appearance of amyloid plaques caus... more Our data indicate that overproduction of A and the consequent appearance of amyloid plaques cause an overall reduction in the number of adult-generated hippocampal neurons. Diminished capacity for hippocampal neuron replacement may contribute to the cognitive decline observed in these mice.
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Papers by Laure Verret