Behavioural effects of extracellular matrix protein Fras1 depletion in the mouse.

Fras1 is an extracellular protein of the basement membranes that surround embryonic epithelia, choroid plexuses and meninges in foetal mouse brain. Depletion of Fras1 in knockout mice results in sub-epidermal blistering and fusion of eyelids and digits as well as malformation of lungs and kidneys. Mutations in the human counterpart FRAS1 are responsible for the Fraser Syndrome with clinical manifestations similar to the murine phenotype. In addition, brain deformities or mental impairments have occasionally been reported in patients with Fraser Syndrome. In the present study, we explored the possible involvement of Fras1 in brain function, analysing its expression pattern in mouse brain and investigating aspects of Fras1-/- mice behaviour, related to the function of brain regions expressing Fras1. Transcripts were detected in choroid plexuses and in certain brain regions including cortical, hippocampal and amygdalar areas in juvenile mice. Behavioural tests revealed that Fras1-/- mice exhibit impaired egocentric spatial memory, aberrant olfactory learning and memory, markedly reduced fear memory in an auditory fear conditioning task, as well as reduced anxiety expression in open field and elevated plus maze tests. Moreover, the extracellular matrix organization has been severely affected in cortical and subcortical areas as demonstrated by Wisteria floribunda agglutinin immunolabelling. The widespread detection of Fras1 transcripts in the brain of both pre- and postnatal mice, as well as the behavioural and cellular disturbances exhibited by Fras1-/- adult mice provide evidence for the involvement of Fras1 in brain organization and function.

Synergistic effects of early life mild adversity and chronic social defeat on rat brain microglia and cytokines.

Exposure to early life stress affects the development and function of the brain and when followed by adversities in adulthood, the negative effects of stress are enhanced. Microglia has been proposed as a potential mediator of this phenomenon. In the present study, we investigated the long-term effects of mild early life stress, the consequences of a stressor in adulthood as well as their interaction on microglial and cytokine (PPARγ, IL-1ß and TNFα) levels in the brain of adult male rats. As an early life stress we used a model of maternal neglect, in which the dam is present but non-accessible to the pup for 15 min during postnatal days 10-13; as a stressor in adulthood we exposed animals to chronic social defeat (CSD) for 3 weeks. We determined in the hippocampus, prefrontal cortex and amygdala, the number of Iba-1+ microglial cells, the number of PPARγ+ cells as well as the relative expression of PPARγ, IL-1ß and TNFα mRNA by qPCR. Following exposure to CSD, the number of Iba-1+ cells was increased in the hippocampus and the prefrontal cortex of adult animals exposed to mild early life stress, while in the absence of CSD no such difference was observed. Moreover, following CSD PPARγ levels were increased in the hippocampus of adult males exposed as neonates to "maternal neglect". Our findings support the notion that early life stress, even a mild one, primes microglia and enhances its reactivity to a second stressful event, later in life, in accord with the "two-hit" hypothesis.

An early experience of mild adversity involving temporary denial of maternal contact affects the serotonergic system of adult male rats and leads to a depressive-like phenotype and inability to adapt to a chronic social stress.

Adverse early life experiences can affect adaptability to chronic stressors and lead to depressive-like behaviors in animal models. We employed an early experience model in which rat pups during postnatal days 10-13 are exposed to a T-maze in which they learn the location of their mother motivated by the rewarding stimulus of maternal contact; one group of rats receives the expected reward, by being allowed contact with the mother upon finding her, while the other group is temporarily denied this contact (Denied Expected Reward, DER), thus experiencing mild adversity. The results presented herein show that the DER early life experience results in a depressive-like phenotype in adulthood, as indicated by the absence of sucrose preference -anhedonia- exhibited by these animals, in adulthood. Following exposure to a chronic social stress (CSS), DER male rats were unable to adapt, evident by reduced general locomotion and time spent in the centre of an open field which indicate anxiety and/or decreased motivation for exploration. They also exhibited increased immobility time in the forced swimming test, suggesting a passive coping strategy. The depressive-like and anxious phenotype of the DER males was accompanied by changes in the serotonergic system, such as lower serotonin levels, higher serotonin turnover and higher levels of the type 1 serotonin receptor in the hippocampus. Our results corroborate findings showing that early life adversity disturbs behavioral regulation in adulthood. They also suggest that even mild adversity, if it involves intervention in mother-offspring interactions, can be sufficient to compromise adaptability.

Increased Anxiety-Related Behavior, Impaired Cognitive Function and Cellular Alterations in the Brain of Cend1-deficient Mice.

Cend1 is a neuronal-lineage specific modulator involved in coordination of cell cycle exit and differentiation of neuronal precursors. We have previously shown that Cend1-/- mice show altered cerebellar layering caused by increased proliferation of granule cell precursors, delayed radial granule cell migration and compromised Purkinje cell differentiation, leading to ataxic gait and deficits in motor coordination. To further characterize the effects of Cend1 genetic ablation we determined herein a range of behaviors, including anxiety and exploratory behavior in the elevated plus maze (EPM), associative learning in fear conditioning, and spatial learning and memory in the Morris water maze (MWM). We observed significant deficits in all tests, suggesting structural and/or functional alterations in brain regions such as the cortex, amygdala and the hippocampus. In agreement with these findings, immunohistochemistry revealed reduced numbers of γ amino butyric acid (GABA) GABAergic interneurons, but not of glutamatergic projection neurons, in the adult cerebral cortex. Reduced GABAergic interneurons were also observed in the amygdala, most notably in the basolateral nucleus. The paucity in GABAergic interneurons in adult Cend1-/- mice correlated with increased proliferation and apoptosis as well as reduced migration of neuronal progenitors from the embryonic medial ganglionic eminence (MGE), the origin of these cells. Further we noted reduced GABAergic neurons and aberrant neurogenesis in the adult dentate gyrus (DG) of the hippocampus, which has been previously shown to confer spatial learning and memory deficits. Our data highlight the necessity of Cend1 expression in the formation of a structurally and functionally normal brain phenotype.

Neural stem/progenitor cells differentiate into oligodendrocytes, reduce inflammation, and ameliorate learning deficits after transplantation in a mouse model of traumatic brain injury.

The central nervous system has limited capacity for regeneration after traumatic injury. Transplantation of neural stem/progenitor cells (NPCs) has been proposed as a potential therapeutic approach while insulin-like growth factor I (IGF-I) has neuroprotective properties following various experimental insults to the nervous system. We have previously shown that NPCs transduced with a lentiviral vector for IGF-I overexpression have an enhanced ability to give rise to neurons in vitro but also in vivo, upon transplantation in a mouse model of temporal lobe epilepsy. Here we studied the regenerative potential of NPCs, IGF-I-transduced or not, in a mouse model of hippocampal mechanical injury. NPC transplantation, with or without IGF-I transduction, rescued the injury-induced spatial learning deficits as revealed in the Morris Water Maze. Moreover, it had beneficial effects on the host tissue by reducing astroglial activation and microglial/macrophage accumulation while enhancing generation of endogenous oligodendrocyte precursor cells. One or two months after transplantation the grafted NPCs had migrated towards the lesion site and in the neighboring myelin-rich regions. Transplanted cells differentiated toward the oligodendroglial, but not the neuronal or astrocytic lineages, expressing the early and late oligodendrocyte markers NG2, Olig2, and CNPase. The newly generated oligodendrocytes reached maturity and formed myelin internodes. Our current and previous observations illustrate the high plasticity of transplanted NPCs which can acquire injury-dependent phenotypes within the host CNS, supporting the fact that reciprocal interactions between transplanted cells and the host tissue are an important factor to be considered when designing prospective cell-based therapies for CNS degenerative conditions.

Exposure to a mildly aversive early life experience leads to prefrontal cortex deficits in the rat.

Aversive early life experiences in humans have been shown to result in deficits in the function of the prefrontal cortex (PFC). In an effort to elucidate possible neurobiological mechanisms involved, we investigated in rats, the effects of a mildly aversive early experience on PFC structure and function. The early experience involved exposure of rat pups during postnatal days (PND) 10-13 to a T-maze in which they search for their mother, but upon finding her are prohibited contact with her, thus being denied the expected reward (DER). We found that the DER experience resulted in adulthood in impaired PFC function, as assessed by two PFC-dependent behavioral tests [attention set-shifting task (ASST) and fear extinction]. In the ASST, DER animals showed deficits specifically in the intra-dimensional reversal shifts and a lower activation-as determined by c-Fos immunohistochemistry-of the medial orbital cortex (MO), a PFC subregion involved in this aspect of the task. Furthermore, the DER experience resulted in decreased glutamatergic neuron and dendritic spine density in the MO and infralimbic cortex (IL) in the adult brain. The decreased neuronal density was detected as early as PND12 and was accompanied by increased micro- and astroglia-density in the MO/IL.

Effects of a Neonatal Experience Involving Reward Through Maternal Contact on the Noradrenergic System of the Rat Prefrontal Cortex.

The noradrenergic system plays an important role in prefrontal cortex (PFC) function. Since early life experiences play a crucial role in programming brain function, we investigated the effects of a neonatal experience involving reward through maternal contact on the noradrenergic system of the rat PFC. Rat pups were exposed during Postnatal days (PNDs) 10-13, to a T-maze in which contact with the mother was used as a reward (RER). RER males had higher norepinephrine levels in the PFC both on PND 13 and in adulthood. The RER experience resulted in adulthood in increased levels of the active demethylase GADD45b, hypomethylation of the ß1 adrenergic receptor (ADRB1) gene promoter, and consequent enhanced expression of its mRNA in the PFC. In addition, protein and binding levels of the ADRB1, as well as those of its downstream effector phosphorylated cAMP response element-binding protein were elevated in RER males. The higher activity of the PFC noradrenergic system of the RER males was reflected in their superior performance in the olfactory discrimination and the contextual fear extinction, 2 PFC noradrenergic system-dependent behavioral tasks.

Rat dams exposed repeatedly to a daily brief separation from the pups exhibit increased maternal behavior, decreased anxiety and altered levels of receptors for estrogens (ERα, ERß), oxytocin and serotonin (5-HT1A) in their brain.

In the present study we investigated the neurobiological mechanisms underlying expression of maternal behavior. Increased maternal behavior was experimentally induced by a brief 15-min separation between the mother and the pups during postnatal days 1 to 22. On postnatal days (PND) 12 and 22, we determined in experimental and control dams levels of anxiety in the elevated plus maze (EPM) as well as the levels of receptors for estrogens (ERα, ERß), oxytocin (OTR) and serotonin (5-HT1AR) in areas of the limbic system (prefrontal cortex-PFC, hippocampus, lateral septum-SL, medial preoptic area-MPOA, shell of nucleus accumbens-nAc-Sh, central-CeA and basolateral-BLA amygdala), involved in the regulation of maternal behavior. Experimental dams, which showed increased maternal behavior towards their offspring, displayed reduced anxiety in the EPM on both PND12 and PND22. These behavioral differences could be attributed to neurochemical alterations in their brain: On both PND12 and PND22, experimental mothers had higher levels of ERα and OTRs in the PFC, hippocampus, CeA, SL, MPOA and nAc-Sh. The experimental manipulation-induced increase in ERß levels was less widespread, being localized in PFC, the hippocampal CA2 area, MPOA and nAc-Sh. In addition, 5-HT1ARs were reduced in the PFC, hippocampus, CeA, MPOA and nAc-Sh of the experimental mothers. Our results show that the experience of the daily repeated brief separation from the pups results in increased brain ERs and OTRs, as well as decreased 5-HT1ARs in the dam's brain; these neurochemical changes could underlie the observed increase in maternal behavior and the reduction of anxiety.

A novel model of early experiences involving neonatal learning of a T-maze using maternal contact as a reward or its denial as an event of mild emotional adversity.

We developed a novel animal model of early life experiences in which rat pups are trained during postnatal days (PND) 10-13 in a T-maze with maternal contact as a reward (RER group) or its denial (DER group) as a mildly aversive event. Both groups of animals learn the T-maze, albeit the RER do so more efficiently. Training results in activation of the basal ganglia in the RER and of the hippocampus and prefrontal cortex in the DER. Moreover, on PND10 DER training leads to increased corticosterone levels and activation of the amygdala. In adulthood, male DER animals show better mnemonic abilities in the Morris water maze while the RER exhibit enhanced fear memory. Furthermore, DER animals have a hypofunctioning serotonergic system and express depressive-like behavior and increased aggression. However, they have increased hippocampal glucocorticoid receptors, indicative of efficient hypothalamic-pituitary-adrenal axis function, and an adaptive pattern of stress-induced corticosterone response. The DER experience with its relatively negative emotional valence results in a complex behavioral phenotype, which cannot be considered simply as adaptive or maladaptive.

Effects of an Early Experience Involving Training in a T-Maze Under either Denial or Receipt of Expected Reward through Maternal Contact.

The mother is the most salient stimulus for the developing pups and a number of early experience models employ manipulation of the mother-infant interaction. We have developed a new model which in addition to changes in maternal behavior includes a learning component on the part of the pups. More specifically, pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. Pups of both experimental groups learn the T-maze, but the RER do so more efficiently utilizing a procedural-type of learning and memory with activation of the dorsal basal ganglia. On the other hand, the DER experience leads to activation of the hippocampus, prefrontal cortex, and amygdala in the pups. In adulthood, male DER animals exhibit better mnemonic abilities in the Morris water maze and higher activation of the hippocampus, while they have decreased brain serotonergic activity, exhibit a depressive-like phenotype and proactive aggressive behavior in the resident-intruder test. While male RER animals assume a reactive coping style in this test, and showed increased freezing during both contextual and cued memory recall following fear conditioning.

Denial or receipt of expected reward through maternal contact during the neonatal period differentially affect the development of the rat amygdala and program its function in adulthood in a sex-dimorphic way.

Early experiences affect brain development and thus adult brain function and behavior. We employed a novel early experience model involving denial (DER) or receipt of expected reward (RER) through maternal contact in a T-maze. Exposure to the DER experience for the first time, on postnatal day 10 (PND10), was stressful for the pups, as assessed by increased corticosterone levels, and was accompanied by enhanced activation of the amygdala, as assessed by c-Fos immunohistochemistry. Re-exposure to the same experience on days 11-13 led to adaptation. Corticosterone levels of the RER pups did not differ on the first and last days of training (PND10 and 13 respectively), while on PND11 and 12 they were lower than those of the CTR. The RER experience did not lead to activation of the amygdala. Males and females exposed as neonates to the DER or RER experience, and controls were tested as adults in the open field task (OF), the elevated plus maze (EPM), and cued and contextual fear conditioning (FC). No group differences were found in the EPM, while in the OF, both male and female DER animals, showed increased rearings, compared to the controls. In the FC, the RER males had increased memory for both context and cued conditioned fear, than either the DER or CTR. On the other hand, the DER males, but not females showed an increased activation, as assessed by c-Fos expression, of the amygdala following fear conditioning. Our results show that the DER early experience programmed the function of the adult amygdala as to render it more sensitive to fearful stimuli. This programming by the DER early experience could be mediated through epigenetic modifications of histones leading to chromatin opening, as indicated by our results showing increased levels of phospho-acetyl-histone-3 in the amygdala of the DER males.

Subventricular zone-derived neural stem cell grafts protect against hippocampal degeneration and restore cognitive function in the mouse following intrahippocampal kainic acid administration.

Temporal lobe epilepsy (TLE) is a major neurological disease, often associated with cognitive decline. Since approximately 30% of patients are resistant to antiepileptic drugs, TLE is being considered as a possible clinical target for alternative stem cell-based therapies. Given that insulin-like growth factor I (IGF-I) is neuroprotective following a number of experimental insults to the nervous system, we investigated the therapeutic potential of neural stem/precursor cells (NSCs) transduced, or not, with a lentiviral vector for overexpression of IGF-I after transplantation in a mouse model of kainic acid (KA)-induced hippocampal degeneration, which represents an animal model of TLE. Exposure of mice to the Morris water maze task revealed that unilateral intrahippocampal NSC transplantation significantly prevented the KA-induced cognitive decline. Moreover, NSC grafting protected against neurodegeneration at the cellular level, reduced astrogliosis, and maintained endogenous granule cell proliferation at normal levels. In some cases, as in the reduction of hippocampal cell loss and the reversal of the characteristic KA-induced granule cell dispersal, the beneficial effects of transplanted NSCs were manifested earlier and were more pronounced when these were transduced to express IGF-I. However, differences became less pronounced by 2 months postgrafting, since similar amounts of IGF-I were detected in the hippocampi of both groups of mice that received cell transplants. Grafted NSCs survived, migrated, and differentiated into neurons-including glutamatergic cells-and not glia, in the host hippocampus. Our results demonstrate that transplantation of IGF-I producing NSCs is neuroprotective and restores cognitive function following KA-induced hippocampal degeneration.

Effects of denial of reward through maternal contact in the neonatal period on adult hypothalamic-pituitary-adrenal axis function in the rat.

Emotional behavioral traits associated with stress response are well documented to be affected by early life events. In the present work, we used a novel paradigm of neonatal experience, in which pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. We then evaluated stress coping and key factors controlling the function of the hypothalamic-pituitary-adrenal axis in adulthood. Adult male DER rats exposed to a single session of forced swim stress (FSS) showed increased immobility, while RER rats exhibited increased escape attempts. The corticosterone response following this stressor was higher although not prolonged in the DER rats. Their CRH mRNA levels in the PVN were increased up to 2h after the forced swim. However, basal levels of these hormones did not differ among groups. In addition, the DER neonatal experience induced an increase in hippocampal GR but a decrease in CRH-R1 immunopositive cells in the CA1 area of the hippocampus and the central amygdala. Overall, these data show a distinct stress response profile in the DER male rats, characterized by passive coping during the forced swim, increased hormonal response following stress, increased inhibitory control through GR and an indirect contribution of CRH-R1, the latter two factors resulting in a modified regulation of the response termination. It thus appears that DER rats have an enhanced potential for appropriate reactivity upon an incoming challenge, while maintaining in parallel an adequate control of the duration of their stress responses.

Effects of an early experience of reward through maternal contact or its denial on laterality of protein expression in the developing rat hippocampus.

Laterality is a basic characteristic of the brain which is detectable early in life. Although early experiences affect laterality of the mature brain, there are no reports on their immediate neurochemical effects during neonatal life, which could provide evidence as to the mechanisms leading to the lateralized brain. In order to address this issue, we determined the differential protein expression profile of the left and right hippocampus of 13-day-old rat control (CTR) pups, as well as following exposure to an early experience involving either receipt (RER) or denial (DER) of the expected reward of maternal contact. Proteomic analysis was performed by 2-dimensional polyacrylamide gel electrophoresis (PAGE) followed by mass spectroscopy. The majority of proteins found to be differentially expressed either between the three experimental groups (DER, RER, CTR) or between the left and right hemisphere were cytoskeletal (34%), enzymes of energy metabolism (32%), and heat shock proteins (17%). In all three groups more proteins were up-regulated in the left compared to the right hippocampus. Tubulins were found to be most often up-regulated, always in the left hippocampus. The differential expression of ß-tubulin, ß-actin, dihydropyrimidinase like protein 1, glial fibrillary acidic protein (GFAP) and Heat Shock protein 70 revealed by the proteomic analysis was in general confirmed by Western blots. Exposure to the early experience affected brain asymmetry: In the RER pups the ratio of proteins up-regulated in the left hippocampus to those in the right was 1.8, while the respective ratio was 3.6 in the CTR and 3.4 in the DER. Our results could contribute to the elucidation of the cellular mechanisms mediating the effects of early experiences on the vulnerability for psychopathology, since proteins shown in our study to be differentially expressed (e.g. tubulins, dihydropyrimidinase like proteins, 14-3-3 protein, GFAP, ATP synthase, α-internexin) have also been identified in proteomic analyses of post-mortem brains from psychiatric patients.

Denial of reward in the neonate shapes sociability and serotonergic activity in the adult rat.

BACKGROUND: Manipulations of the early environment are linked to long-lasting alterations of emotionality and social capabilities. Denial of rewarding mother-pup interactions in early life of rats could serve as model for child neglect. Negative consequences for social competence in later life, accompanied by changes in the serotonergic system would be expected. In contrast, rewarding mother-pup contact should promote adequate social abilities. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats trained in a T-maze during postnatal days 10-13 under denial (DER) or permission (RER) of maternal contact were tested for play behavior in adolescence and for coping with defeat in adulthood. We estimated serotonin (5-HT) levels in the brain under basal conditions and following defeat, as well as serotonin receptor 1A (5-HT1A) and serotonin transporter (SERT) expression. DER rats exhibited increased aggressive-like play behavior in adolescence (i.e. increased nape attacks, p<0.0001) and selected a proactive coping style during defeat in adulthood (higher sum of proactive behaviors: number of attacks, flights, rearings and defensive upright posture; p = 0.011, p<0.05 vs RER, non-handled-NH). In adulthood, they had lower 5-HT levels in both the prefrontal cortex (p<0.05 vs RER) and the amygdala (p<0.05 vs NH), increased 5-HT levels following defeat (PFC p<0.0001) and decreased serotonin turnover (amygdala p = 0.008). The number of 5-HT1A immunopositive cells in the CA1 hippocampal area was increased (p<0.05 DER, vs RER, NH); SERT levels in the amygdala were elevated (p<0.05 vs RER, NH), but were lower in the prefrontal cortex (p<0.05 vs NH). CONCLUSIONS/SIGNIFICANCE: Denial of expected maternal reward early in life negatively affects sociability and the serotonergic system in a complex manner. We propose that our animal model could contribute to the identification of the neurobiological correlates of early neglect effects on social behavior and coping with challenges, but also in parallel with the effects of a rewarding early-life environment.

Enhanced neuronal plasticity and elevated endogenous sAPPα levels in mice over-expressing MMP9.

Evidence accumulating during the past few years points to a significant role of matrix metalloproteinase 9 (MMP9) enzymatic activity in synaptic plasticity and cognitive processes. We have previously demonstrated that MMP9 is involved in receptor-mediated α-secretase-like cleavage of APP in vitro, resulting in increased secretion of sAPPα, the soluble N-terminal product of the non-amyloidogenic pathway known to be involved in neuronal plasticity and memory formation. To study the in vivo role of MMP9, we have generated transgenic mice over-expressing MMP9 in the brain. Herein, we demonstrate that MMP9 transgenic animals display enhanced performance in the non-spatial novel object recognition and the spatial water-maze task and that their enhanced performance was accompanied by increased dendritic spine density in the hippocampus and cortex following behavioural testing. Consistent with the above observations, the electrophysiological analysis revealed prolonged maintenance of long-term synaptic potentiation in hippocampal slices from MMP9 transgenic mice. Moreover, elevated sAPPα levels in the hippocampus and cortex of MPP9 transgenic animals were also observed. Overall, our results extend previous findings on the physiological role of MMP9 in neuronal plasticity and furthermore reveal that, APP may be one of the physiological proteolytic targets of MMP9 in vivo.

IGF-I ameliorates hippocampal neurodegeneration and protects against cognitive deficits in an animal model of temporal lobe epilepsy.

Epilepsy is a major neurological disease, and patients often show spatial memory deficits. Thus, there is a need of effective new therapeutic approaches. IGF-I has been shown to be neuroprotective following a number of experimental insults to the nervous system, and in a variety of animal models of neurodegenerative diseases. In the present work, we investigated the possible neuroprotective effects of IGF-I following unilateral intrahippocampal administration of kainic acid (KA), an animal model of temporal lobe epilepsy (TLE). KA induced cell death, as shown by FluoroJade B, and extensive cell loss in both the ipsilateral and contralateral CA3 and CA4 areas, as well as granule cell dispersal in the DG, as revealed by Cresyl violet staining. KA also resulted in intense astrogliosis and microgliosis, as assessed by the number of GFAP and CD11b immunopositive cells, respectively, and increased hippocampal neurogenesis. Exposure to the Morris Water Maze task revealed that mice injected with KA were deficient in spatial learning and both short- and long-term memories, when tested in a larger diameter pool, which requires the use of allocentric strategies. When tested in a smaller pool, only long-term memory was impaired. Administration of IGF-I decreased seizure severity, hippocampal neurogenesis, and protected against neurodegeneration at the cellular level as assessed by FluoroJade B and Cresyl violet staining, as well as the number of GFAP and CD11b immunopositive cells. Furthermore, IGF-I abolished the cognitive deficits. Our results support that IGF-I could have a possible therapeutic potential in TLE.

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model.

Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein receptor that regulates cholesterol efflux from the peripheral tissues to the liver. SR-BI has been identified on astrocytes and vascular smooth muscle cells in Alzheimer's disease brain and has been shown to mediate adhesion of microglia to fibrillar amyloid-ß (Aß). Here we report that SR-BI mediates perivascular macrophage response and regulates Aß-related pathology and cerebral amyloid angiopathy in an Alzheimer's mouse model. Reduction or deletion of SR-BI gene in heterozygous or homozygous deficient mice (SR-BI(+/-), (-/-)) resulted in a significant increase in perivascular macrophages in the brain. SR-BI deletion had no effect on apolipoprotein E or apolipoprotein AI levels in the mouse brain. Our analysis revealed increased levels of SR-BI expression in the brains of human amyloid precursor protein (Swedish, Indiana) transgenic mice (J20 line). To evaluate the role of SR-BI in Alzheimer's disease pathogenesis, we inactivated one SR-BI allele in J20 transgenic mice. SR-BI reduction in J20/SR-BI(+/-) mice enhanced fibrillar amyloid deposition and cerebral amyloid angiopathy and also exacerbated learning and memory deficits compared with J20 littermates. Immunohistochemical analysis revealed localization of SR-BI on perivascular macrophages in tight association with Aß deposits. Our data suggest that SR-BI reduction impairs the response of perivascular macrophages to Aß and enhances the Aß-related phenotype and cerebral amyloid angiopathy in J20 mice. These results reveal that SR-BI, a scavenger receptor primarily involved in high-density lipoprotein cholesterol transport, plays an essential role in Alzheimer's disease and cerebral amyloid angiopathy.

The expression of TAG-1 in glial cells is sufficient for the formation of the juxtaparanodal complex and the phenotypic rescue of tag-1 homozygous mutants in the CNS.

Myelinated fibers are organized into specialized domains that ensure the rapid propagation of action potentials and are characterized by protein complexes underlying axoglial interactions. TAG-1 (Transient Axonal Glycoprotein-1), a cell adhesion molecule of the Ig superfamily, is expressed by neurons as well as by myelinating glia. It is essential for the molecular organization of myelinated fibers as it maintains the integrity of the juxtaparanodal region through its interactions with Caspr2 and the voltage-gated potassium channels (VGKCs) on the axolemma. Since TAG-1 is the only known component of the juxtaparanodal complex expressed by the glial cell, it is important to clarify its role in the molecular organization of juxtaparanodes. For this purpose, we generated transgenic mice that exclusively express TAG-1 in oligodendrocytes and lack endogenous gene expression (Tag-1(-/-);plp(Tg(rTag-1))). Phenotypic analysis clearly demonstrates that glial TAG-1 is sufficient for the proper organization and maintenance of the juxtaparanodal domain in the CNS. Biochemical analysis shows that glial TAG-1 physically interacts with Caspr2 and VGKCs. Ultrastructural and behavioral analysis of Tag-1(-/-);plp(Tg(rTag-1)) mice shows that the expression of glial TAG-1 is sufficient to restore the axonal and myelin deficits as well as the behavioral defects observed in Tag-1(-/-) animals. Together, these data highlight the pivotal role of myelinating glia on axonal domain differentiation and organization.

Lentivirus-mediated expression of insulin-like growth factor-I promotes neural stem/precursor cell proliferation and enhances their potential to generate neurons.

Strategies to enhance neural stem/precursor cell (NPC) capacity to yield multipotential, proliferative, and migrating pools of cells that can efficiently differentiate into neurons could be crucial for structural repair after neurodegenerative damage. Here, we have generated a lentiviral vector for expression of insulin-like growth factor-I (IGF-1) and investigated the impact of IGF-1 transduction on the properties of cultured NPCs (IGF-1-NPCs). Under proliferative conditions, IGF-1 transduction promoted cell cycle progression via cyclin D1 up-regulation and Akt phosphorylation. Remarkably upon differentiation-inducing conditions, IGF-1-NPCs cease to proliferate and differentiate to a greater extent into neurons with significantly longer neurites, at the expense of astrocytes. Moreover, using live imaging we provide evidence that IGF-1 transduction enhances the motility and tissue penetration of grafted NPCs in cultured cortical slices. These results illustrate the important consequence of IGF-1 transduction in regulating NPC functions and offer a potential strategy to enhance the prospective repair potential of NPCs.