Shedding of neurexin 3β ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons.

Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3β is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease γ-secretase, producing secreted neurexin3β (sNrxn3β) and a single intracellular domain (Nrxn3β-ICD). We further completed the full characterization of the sites at which Nrxn3β is processed by these proteases. Supporting the physiological relevance of the Nrxn3β processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3β on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3β produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3β produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3β in plasticity and network remodeling during neuronal development

Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement

A small peptide from a neuronal cell adhesion molecule enhances synaptic plasticity in the hippocampus and results in improved cognitive performance in rats

Adolescent exposure to nicotine and/or the cannabinoid agonist CP 55,940 induces gender-dependent long lasting memory impairments and changes in brain nicotinic and CB1 cannabinoid receptors

We have analysed the long-term effects of adolescent (postnatal day 28-43) exposure of male and female rats to nicotine (NIC, 1.4 mg/kg/day) and/or the cannabinoid agonist CP 55,940 (CP, 0.4 mg/kg/day) on the following parameters measured in the adulthood: (1) the memory ability evaluated in the object location task (OL) and in the novel object test (NOT); (2) the anxiety-like behaviour in the elevated plus maze; and (3) nicotinic and CBI cannabinoid receptors in cingulated cortex and hippocampus. In the OL, all pharmacological treatments induced significant decreases in the DI of females, whereas no significant effects were found among males. In the NOT, NIC-treated females showed a significantly reduced DI, whereas the effect of the cannabinoid agonist (a decrease in the DI) was only significant in males. The anxiety-related behaviour was not changed by any drug. Both, nicotine and cannabinoid treatments induced a long-lasting increase in CBI receptor activity (CP-stimulated GTP gamma S binding) in male rats, and the nicotine treatment also induced a decrease in nicotinic receptor density in the prefrontal cortex of females. The results show gender-dependent harmful effects of both drugs and long-lasting changes in CBI and nicotinic receptors

Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats

We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 μg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower dose induced anxiolytic-like responses. The 5-HT1A antagonist, which was silent in this test, attenuated the anxiogenic, but not the anxiolytic, effect of CP 55,940. In the holeboard, the higher dose of CP 55,940 significantly decreased head-dipping duration, and WAY 100635, which did not affect exploratory head-dipping when administered alone, antagonized this effect. The administration of WAY 100635 significantly increased grooming behaviour, and this effect was inhibited by the two doses of CP 55,940, which did not exert any effect, per se, on this parameter. We provide the first evidence implicating 5-HT1A receptors in anxiety-related behavioural responses to a cannabinoid agonist. © 2004 Lippincott Williams & Wilkins.Peer Reviewe

Long Term Sex-Dependent Psychoneuroendocrine Effects of Maternal Deprivation and Juvenile Unpredictable Stress in Rats

We have analysed the long-term psychoneuroendocrine effects of maternal deprivation (MD) [24 h at postnatal day (PND) 9] and/or exposure to chronic unpredictable stress (CUS) during the periadolescent period (PND 28 to PND 43) in male and female Wistar rats. Animals were tested in the elevated plus maze (EPM, anxiety) at PND 44 and in two memory tests, spontaneous alternation and novel object recognition (NOT) in adulthood. The expression of hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, as well as of synaptophysin, neural cell adhesion molecule and brain-derived neurotrophic factor, was analysed by in situ hybridisation in selected hippocampal regions. Endocrine determinations of leptin, testosterone and oestradiol plasma levels were carried out by radioimmunoassay. Young CUS animals showed decreased anxiety behaviour in the EPM (increased percentage of time and entries in the open arms) irrespective of neonatal treatment. Memory impairments were induced by the two stressful treatments as was revealed by the NOT, with males being most clearly affected. Although each stressful procedure, when considered separately, induced different (always decrements) effects on the three synaptic molecules analysed and affected males and females differently, the combination of MD and CUS induced an unique disruptive effect on the three synaptic plasticity players. MD induced a long-term significant decrease in hippocampal GR only in males, whereas CUS tended to increase MR in males and decrease MR in females. Both neonatal MD and periadolescent CUS induced marked reductions in testosterone and oestradiol in males, whereas MD male animals also showed significantly decreased leptin levels. By contrast, in females, none of the hormones analysed was altered by any of the stressful procedures. Taking our data together in support of the 'two-hit' hypothesis, MD during neonatal life and/or exposure to CUS during the periadolescent period induced a permanent deficit in memory, which was accompanied by a decrement in markers for hippocampal plasticity. The long-term effects on body weight and hormone levels, particularly among males, might reflect sex-dependent lasting metabolic alterations as well as an impaired reproductive function.Diabetes mellitus: pathophysiological changes and therap

Behavioral, endocrine and immunological characteristics of a murine model of premature aging

We have previously shown that differences in life span among members of Swiss mouse populations appear to be related to their exploration of a T-maze, with a slow exploration ('slow mice') being linked to alteration of spontaneous behavior and monoaminergic systems, impaired immune function and shorter life span. In general these traits resemble some of the characteristics of chronologically old animals. Thus, we proposed the 'slow mice' as a model of prematurely aging mice (PAM). Now, we have compared female PAM with non-prematurely aging mice (NPAM) as regards a number of behavioral, endocrine and immunological parameters which were studied under both basal and stress conditions. In the present study the animals were chronologically younger than those used in our previous work. When compared to NPAM, the PAM showed increased anxiogenic-like responses in the plus-maze, increased basal corticosterone levels and decreased corticosterone responses to stress. The PAM also showed a decreased natural killer activity as well as decreased lymphoproliferative responses to mitogens. Moreover, the mitogen-induced lymphoproliferative responses of the PAM appeared to be more susceptible to stress. The data indicate that certain characteristics of the PAM are already present in animals of very young chronological age and provide new information for a more complete characterization of the PAM from a neuroimmunoendocrine viewpoint. © 2005 Elsevier Ltd. All rights reserved.Peer Reviewe

Long term sex-dependent psychoneuroendocrine effects of maternal deprivation and juvenile unpredictable stress in rats

We have analysed the long-term psychoneuroendocrine effects of maternal deprivation (MD) [24 h at postnatal day (PND) 9] and/or exposure to chronic unpredictable stress (CUS) during the periadolescent period (PND 28 to PND 43) in male and female Wistar rats. Animals were tested in the elevated plus maze (EPM, anxiety) at PND 44 and in two memory tests, spontaneous alternation and novel object recognition (NOT) in adulthood. The expression of hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, as well as of synaptophysin, neural cell adhesion molecule and brain-derived neurotrophic factor, was analysed by in situ hybridisation in selected hippocampal regions. Endocrine determinations of leptin, testosterone and oestradiol plasma levels were carried out by radioimmunoassay. Young CUS animals showed decreased anxiety behaviour in the EPM (increased percentage of time and entries in the open arms) irrespective of neonatal treatment. Memory impairments were induced by the two stressful treatments as was revealed by the NOT, with males being most clearly affected. Although each stressful procedure, when considered separately, induced different (always decrements) effects on the three synaptic molecules analysed and affected males and females differently, the combination of MD and CUS induced an unique disruptive effect on the three synaptic plasticity players. MD induced a long-term significant decrease in hippocampal GR only in males, whereas CUS tended to increase MR in males and decrease MR in females. Both neonatal MD and periadolescent CUS induced marked reductions in testosterone and oestradiol in males, whereas MD male animals also showed significantly decreased leptin levels. By contrast, in females, none of the hormones analysed was altered by any of the stressful procedures. Taking our data together in support of the 'two-hit' hypothesis, MD during neonatal life and/or exposure to CUS during the periadolescent period induced a permanent deficit in memory, which was accompanied by a decrement in markers for hippocampal plasticity. The long-term effects on body weight and hormone levels, particularly among males, might reflect sex-dependent lasting metabolic alterations as well as an impaired reproductive function

Functional responses to the cannabinoid agonist WIN 55,212-2 in neonatal rats of both genders: influence of weaning

19 pages, 5 figures. - PMID: 15251268 [PubMed - indexed for MEDLINE]We have studied behavioural, biochemical and endocrine responses to the cannabinoid agonist WIN 55,212-2 (WIN) in neonatal rats, as well as the effects of weaning on such responses. We used preweanling rats (20 days of age), 25-day-old weaned rats (weaning at Day 22) and 25-day-old nonweaned rats of both sexes. The behavioural effects of WIN were assessed in the nociceptive tail immersion test and in the open field. We also analysed the effect of weaning on corticosterone responses to WIN (radioimmunoassay) as well as on WIN-stimulated [35S] GTPgammaS binding in periaqueductal grey (PAG) and striatum. The cannabinoid agonist induced a modest increase in pain thresholds, whereas the effect of the drug on open-field activity, particularly on vertical activity, was much more marked. The weaning process appeared to reduce the baseline nociceptive latencies of the female rats. No significant effect of weaning on the behavioural responses to WIN was found. However, the group of weaned females (but not males) showed a significantly reduced WIN-stimulated [35S] GTPgammaS binding in the striatum. The cannabinoid agonist significantly increased the corticosterone levels of 25-day-old rats with the effect being more marked in weaned than in nonweaned animals. The results suggest that the weaning process might produce some sexually dimorphic developmental changes in CB1 receptor functionThis study was supported by the Ministerio de Ciencia y Tecnología (BFI2000-0611)Peer reviewe