Papers by Federica Premoselli
Pharmacological Research, 2016
Plos One, 2009
Glutamate receptor delta 2 (GluRdelta2) is selectively expressed in the cerebellum, exclusively i... more Glutamate receptor delta 2 (GluRdelta2) is selectively expressed in the cerebellum, exclusively in the spines of the Purkinje cells (PCs) that are in contact with parallel fibers (PFs). Although its structure is similar to ionotropic glutamate receptors, it has no channel function and its ligand is unknown. The GluRdelta2-null mice, such as knockout and hotfoot have profoundly altered cerebellar circuitry, which causes ataxia and impaired motor learning. Notably, GluRdelta2 in PC-PF synapses regulates their maturation and strengthening and induces long term depression (LTD). In addition, GluRdelta2 participates in the highly territorial competition between the two excitatory inputs to the PC; the climbing fiber (CF), which innervates the proximal dendritic compartment, and the PF, which is connected to spiny distal branchlets. Recently, studies have suggested that GluRdelta2 acts as an adhesion molecule in PF synaptogenesis. Here, we provide in vivo and in vitro evidence that supports this hypothesis. Through lentiviral rescue in hotfoot mice, we noted a recovery of PC-PF contacts in the distal dendritic domain. In the proximal domain, we observed the formation of new spines that were innervated by PFs and a reduction in contact with the CF; ie, the pattern of innervation in the PC shifted to favor the PF input. Moreover, ectopic expression of GluRdelta2 in HEK293 cells that were cocultured with granule cells or in cerebellar Golgi cells in the mature brain induced the formation of new PF contacts. Collectively, our observations show that GluRdelta2 is an adhesion molecule that induces the formation of PF contacts independently of its cellular localization and promotes heterosynaptic competition in the PC proximal dendritic domain.
Bollettino della Società italiana di biologia sperimentale
Aberrant crypt foci (ACF) are putative preneoplastic lesions of colon cancer which are being util... more Aberrant crypt foci (ACF) are putative preneoplastic lesions of colon cancer which are being utilized currently as a biological end point to evaluate the induction and modulation of colon carcinogenesis. In rodents, caloric restriction reduces carcinogen-induced colon cancer incidence. The present study was designed to investigate the effect of fasting followed by refeeding on the development of ACF. Male Fisher 344 rats were fasted for 4 days and they were given a single injection of azoxymethane (AOM) at the dose of 20 mg/kg body weight on the first day of refeeding, and killed 3 months later. Controls were fed ad libitum and received the same dose of AOM. The number and crypt multiplicity (number of crypts/focus) of ACF were measured on the medial colon. No effect of fasting/refeeding was observed in the total number of foci/medial colon. On the contrary, rats fasted for 4 days and refed developed foci with higher number of crypts than fed controls. Our results are of particular interest because the crypt multiplicity, rather than the number of foci, is a consistent predictor of tumor incidence. As a consequence these data suggest a possible role of fasting/refeeding in enhancing the colon tumor outcome.
Bollettino della Società italiana di biologia sperimentale
ABSTRACT
Bollettino della Società italiana di biologia sperimentale
We have recently shown that fasting before initiation markedly stimulated the growth of aberrant ... more We have recently shown that fasting before initiation markedly stimulated the growth of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in the rat medial colon. Here we investigated the mechanisms by which fasting enhanced the growth of ACF. Rats were exposed to 4 day-starvation, then they were given AOM (20 mg/kg) on the first day of refeeding. 4 day-fasting depressed cell proliferation as shown by the decreased mitotic index and enhanced cell death by apoptosis. On the first day of refeeding, apoptotic index remained higher than control values, while mitotic index markedly increased in the colonic epithelium of fasted/ refed rats. The administration of AOM induced an apoptotic wave, that was higher in controls, and a transient drop in the mitotic index that recovered quickly in the fasted/refed group. These data suggest that starvation-induced apoptosis represents the mitogenic stimulus to increase the rates of cell proliferation responsible for the enhanced growth of ACF in fasted/refed rats.
PLoS ONE, 2009
Glutamate receptor delta 2 (GluRd2) is selectively expressed in the cerebellum, exclusively in th... more Glutamate receptor delta 2 (GluRd2) is selectively expressed in the cerebellum, exclusively in the spines of the Purkinje cells (PCs) that are in contact with parallel fibers (PFs). Although its structure is similar to ionotropic glutamate receptors, it has no channel function and its ligand is unknown. The GluRd2-null mice, such as knockout and hotfoot have profoundly altered cerebellar circuitry, which causes ataxia and impaired motor learning. Notably, GluRd2 in PC-PF synapses regulates their maturation and strengthening and induces long term depression (LTD). In addition, GluRd2 participates in the highly territorial competition between the two excitatory inputs to the PC; the climbing fiber (CF), which innervates the proximal dendritic compartment, and the PF, which is connected to spiny distal branchlets. Recently, studies have suggested that GluRd2 acts as an adhesion molecule in PF synaptogenesis. Here, we provide in vivo and in vitro evidence that supports this hypothesis. Through lentiviral rescue in hotfoot mice, we noted a recovery of PC-PF contacts in the distal dendritic domain. In the proximal domain, we observed the formation of new spines that were innervated by PFs and a reduction in contact with the CF; ie, the pattern of innervation in the PC shifted to favor the PF input. Moreover, ectopic expression of GluRd2 in HEK293 cells that were cocultured with granule cells or in cerebellar Golgi cells in the mature brain induced the formation of new PF contacts. Collectively, our observations show that GluRd2 is an adhesion molecule that induces the formation of PF contacts independently of its cellular localization and promotes heterosynaptic competition in the PC proximal dendritic domain.
PLoS ONE, 2011
Eph receptor tyrosine kinases are involved in many cellular processes. In the developing brain, t... more Eph receptor tyrosine kinases are involved in many cellular processes. In the developing brain, they act as migratory and cell adhesive cues while in the adult brain they regulate dendritic spine plasticity. Here we show a new role for Eph receptor signalling in the cerebellar cortex. Cerebellar Purkinje cells are innervated by two different excitatory inputs. The climbing fibres contact the proximal dendritic domain of Purkinje cells, where synapse and spine density is low; the parallel fibres contact the distal dendritic domain, where synapse and spine density is high. Interestingly, Purkinje cells have the intrinsic ability to generate a high number of spines over their entire dendritic arborisations, which can be innervated by the parallel fibres. However, the climbing fibre input continuously exerts an activity-dependent repression on parallel fibre synapses, thus confining them to the distal Purkinje cell dendritic domain. Such repression persists after Eph receptor activation, but is overridden by Eph receptor inhibition with EphA4/Fc in neonatal cultured cerebellar slices as well as mature acute cerebellar slices, following in vivo infusion of the EphA4/Fc inhibitor and in EphB receptor-deficient mice. When electrical activity is blocked in vivo by tetrodotoxin leading to a high spine density in Purkinje cell proximal dendrites, stimulation of Eph receptor activation recapitulates the spine repressive effects of climbing fibres. These results suggest that Eph receptor signalling mediates the repression of spine proliferation induced by climbing fibre activity in Purkinje cell proximal dendrites. Such repression is necessary to maintain the correct architecture of the cerebellar cortex.
Nutrition and Cancer, 1998
The effect of fasting-refeeding during the promotion phase of dimethylbenz[a]anthracene (DMBA)-in... more The effect of fasting-refeeding during the promotion phase of dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis has been investigated. Female Sprague-Dawley rats were given 130 mg/kg of DMBA and divided into four groups: Group 1 was fed ad libitum; Group 2 was fed ad libitum and, in addition, received daily subcutaneous injections of beta-estradiol and haloperidol for eight days, beginning two weeks after DMBA administration; Group 3 was exposed to three days of fasting one week after carcinogen injection, then fed ad libitum until the end of the experiment; Group 4 was treated as Group 2, except the animals were fasted for three days beginning one week after DMBA administration. Treatment with beta-estradiol and haloperidol enhanced the development of DMBA-induced mammary tumors. Rats fasted after DMBA administration showed increased genesis and growth and reduced latency of mammary tumors. Fasting before beta-estradiol and haloperidol injection resulted in a more pronounced effect on tumor yield and latency than hormones or fasting alone. The data indicate that, in rats fasted during the promotion phase, tumor growth is enhanced and the permissive effects of hormones on mammary carcinogenesis are potentiated.
Nanotoxicology, 2012
We studied the effects of multi-walled carbon nanotubes (MWCNTs) on the electrophysiological prop... more We studied the effects of multi-walled carbon nanotubes (MWCNTs) on the electrophysiological properties of cultured mouse chromaffin cells, a model of spontaneously firing cells. The exposure of chromaffin cells to MWCNTs at increasing concentrations (30-263 mg/ml) for 24 h reduced, in a dose-dependent way, both the cell membrane input resistance and the number of spontaneously active cells (from 80-52%). Active cells that survived from the toxic effects of MWCNTs exhibited more positive resting potentials, higher firing frequencies and unaltered voltage-gated Ca 2+ , Na + and K+ current amplitudes. MWCNTs slowed down the inactivation kinetics of Ca 2+ -dependent BK channels. These electrophysiological effects were accompanied by MWCNTs internalization, as confirmed by transmission electron microscopy, indicating that most of the toxic effects derive from a dose-dependent MWCNTs-cell interaction that damages the spontaneous cell activity.
International Journal of Cancer, 1998
In contrast to the protective effect of chronic caloric restriction on tumor development, we have... more In contrast to the protective effect of chronic caloric restriction on tumor development, we have shown that fasting sustained tumor initiation in rat liver by a noninitiating dose of diethylnitrosamine. Here we investigated whether fasting had a similar favorable effect on initiation in the colorectal mucosa in 80 male F344 rats. Animals fasted for 4 days were given a single s.c. dose of azoxymethane (AOM) (20 mg/kg) on the first day of re-feeding, and rates of kinetic proliferative parameters, and development of the pre-neoplastic lesions such as aberrant crypt foci (ACF), were evaluated. Starvation before AOM treatment enhanced the growth of ACF, as shown by the significantly higher crypt multiplicity of fasted/re-fed rats as compared with fully fed rats (3.97 +/- 0.50 vs. 2.64 +/- 0.20, p < or = 0.025). This difference was associated with perturbations in cell death and cell proliferation. Fasting induced apoptosis and depressed cell division, while re-feeding had opposite effects, resulting in a higher percentage of S-phase cells at the time of AOM injection and 2 days thereafter. Starvation-induced apoptosis may represent the mitogenic stimulus to an increase in the number of cells susceptible to AOM damage, and may favor its fixation, leading to enhanced growth of ACF. Our data therefore suggest that fasting/re-feeding enhances colon cancer.
PLoS ONE, 2013
Epileptic activity is generally induced in experimental models by local application of epileptoge... more Epileptic activity is generally induced in experimental models by local application of epileptogenic drugs, including pentylenetetrazol (PTZ), widely used on both vertebrate and invertebrate neurons. Despite the high prevalence of this neurological disorder and the extensive research on it, the cellular and molecular mechanisms underlying epileptogenesis still remain unclear. In this work, we examined PTZ-induced neuronal changes in Helix monosynaptic circuits formed in vitro, as a simpler experimental model to investigate the effects of epileptiform activity on both basal release and post-tetanic potentiation (PTP), a form of short-term plasticity. We observed a significant enhancement of basal synaptic strength, with kinetics resembling those of previously described use-dependent forms of plasticity, determined by changes in estimated quantal parameters, such as the readily releasable pool and the release probability. Moreover, these neurons exhibited a strong reduction in PTP expression and in its decay time constant, suggesting an impairment in the dynamic reorganization of synaptic vesicle pools following prolonged stimulation of synaptic transmission. In order to explain this imbalance, we determined whether epileptic activity is related to the phosphorylation level of synapsin, which is known to modulate synaptic plasticity. Using western blot and immunocytochemical staining we found a PTZ-dependent increase in synapsin phosphorylation at both PKA/CaMKI/IV and MAPK/Erk sites, both of which are important for modulating synaptic plasticity. Taken together, our findings suggest that prolonged epileptiform activity leads to an increase in the synapsin phosphorylation status, thereby contributing to an alteration of synaptic strength in both basal condition and tetanusinduced potentiation.
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Papers by Federica Premoselli