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Meccanismi di modulazione presinaptica nei neuroni dopaminergici della substantia nigra pars compacta
Full text linkL’inibizione presinaptica è un meccanismo di modulazione sinaptica comunemente osservato nelle sinapsi del sistema nervoso centrale e periferico. Questo processo inizia in risposta all’attivazione di un’ampia varietà di recettori presinaptici e porta ad una riduzione della probabilità di fusione delle vescicole con la membrana del terminale sinaptico. Uno dei più comuni meccanismi d’azione consiste nell’inibizione dei canali del calcio voltaggio dipendenti (VDCCs) localizzati nei bottoni presinaptici. Tuttavia, esistono altre forme di inibizione presinaptica con meccanismi che coinvolgono direttamente la machinery di rilascio vescicolare. In questa tesi ho studiato il meccanismo di inibizione presinaptica mediata dal recettore metabotropico del glutammato del tipo III (mGluRs) e dal recettore GABAB nella trasmissione GABAergica dei neuroni dopaminergici della substantia nigra pars compacta (SNc) di ratto. L’AP-4 (100 μM), agonista selettivo del recettore metabotropico del glutammato del tipo III, e il baclofen (10 μM), agonista selettivo del recettore GABAB, riducono reversibilmente la frequenza delle correnti spontanee inibitorie post-sinaptiche (sIPSCs) rispettivamente del 48.5 ± 3.7 % e del 83.6 ± 2.3 % rispetto al controllo, senza avere alcun effetto sull’ampiezza della corrente. L’AP-4, non deprime la frequenza delle correnti inibitorie miniature post-sinaptiche (mIPSCs), registrate in tetrodotossina (TTX, 1 μM) e cadmio (100 μM), mentre è in grado di ridurre la frequenza delle mIPSCs del 75.3 ± 2.8 % rispetto al controllo, in presenza di TTX (1 μM) e bario (1 mM). Al contrario, il baclofen riduce la frequenza delle mIPSCs sia in cadmio (70.0 ± 6.7 % del controllo) sia in bario (52.3 ± 2.9 % del controllo). In TTX e ionomicina (2 μM), il baclofen riduce significativamente la frequenza delle mIPSCs del 71.8 ± 6.9 % del controllo, mentre l’AP-4 non ha effetto. In maniera simile, in presenza di TTX e α-latrotossina (α-LTX, 0.3 nM), la frequenza delle mIPSCs è diminuita del 64.5 ± 4.8 % del controllo dal baclofen, mentre mantiene gli stessi valori in presenza di AP-4. Infine, in continua presenza di baclofen, l’AP-4 non causa un ulteriore riduzione della frequenza delle sIPSCs. La conclusione di questi studi è che i recettori metabotropici del glutammato del tipo III deprimono il rilascio di GABA dai neuroni dopaminergici della SNc , attraverso l’inibizione dei VDCC, mentre i recettori presinaptici GABAB coinvolgono direttamente il rilascio vescicolare del neurotrasmettitore. Inoltre questi due diversi meccanismi di inibizione pre-sinaptica coesistono nello stesso terminale sinaptico. Questa caratterizzazione fornisce nuove conoscenze sul ruolo di questi recettori presinaptici nello studio della fisiologia della substantia nigra e nel loro potenziale uso come target nel trattamento farmacologico di malattie neurodegenerative come il morbo di Parkinson.Presynaptic inhibition is a mechanism of synaptic modulation normally observed in the synapses of the nervous system. This process starts upon activation of a large number of presynaptic receptors and leads to the decreased probability of vesicles to fuse to the cell membrane. One of the most common mechanism consists in the inhibition of the voltage dependent calcium channels (VDCC) located on the active zone of the presynaptic neuron. However, there is evidence for another form of presynaptic inhibition with a direct impairment of the vescicular release machinery. In my thesis I have investigated the mechanisms of presynaptic inhibition by group III metabotropic glutamate receptors (mGluRs) and GABAB receptors of the GABAergic neurotransmission to dopamine (DA) neurones of the rat substantia nigra pars compacta (SNc). The group III mGluRs agonist L-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 μM) and the GABAB receptor agonist baclofen (10 μM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 ± 3.7 % and 83.6 ± 2.3 % of control, respectively, with no effect in their amplitude. AP4 did not affect miniature inhibitory postsynaptic currents (mIPSCs) recorded in tetrodotoxin (TTX, 1 μM) and cadmium (100 μM), while in TTX (1 μM) and barium (1 mM), mIPSCs frequency was reduced to 75.3 ± 2.8 % of control. In contrast, baclofen reduced mIPSCs frequency either in cadmium (70.0 ± 6.7 % of control) or barium (52.3 ± 2.9 % of control). In TTX and ionomycin (2 μM), baclofen significantly reduced mIPSCs frequency to 71.8 ± 6.9 % of control, while AP4 had no effect. Similarly, in TTX and α-latrotoxin (α-LTX, 0.3 nM), the frequency of mIPSCs was reduced by baclofen to 64.5 ± 4.8 % of control, but was insensitive to AP4. Finally, in the continuous presence of baclofen, AP4 failed to produce any further reduction of sIPSCs frequency. The conclusion of this study is that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic voltage-dependent calcium channels, while presynaptic GABAB receptors also impair transmitter exocytosis, and both mechanisms coexist on the same synapses. This characterization provides new insights about the role of these presynaptic receptors in the physiology of the substantia nigra and their potential involvement in the treatment of neurodegenerative diseases such as Parkinson’s Disease
Expression of neurotrophin receptors in the developing and adult testis
No full textNerve growth factor (NGF) and the other members of the family of neurotrophic factors (the neurotrophin) are essential for neuronal development and differentiation. Neurotrophins interact with two types of cell surface receptors: a low-affinity receptor (p75 NGF-R) and a high-affinity tyrosine kinase receptor belonging to the trk proto-oncogene family, both expressed in the nervous system and in certain non-neuronal tissues. Recently, NGF immunoreactivity and mRNA have been detected in the testis of the adult mouse, rat and human. In the present report we demonstrate the expression of p75 NGF-R during early gonadal development, by mesenchymal cells of the embryonic mouse and rat testis. In the embryonic testis p75 NGF-R-positive cells are spread through the interstitial compartment; during postnatal development they become organized in a cellular layer that surrounds differentiating myoid cells of the seminiferous tubule. Our results also show the expression in the peripuberal and adult mouse and rat testis, of an abundant and shorter transcript of 3.2 kb that cross-hybridizes to the receptor mRNA (3.7 kb). This new mRNA species, which appears at the beginning of spermatogenesis, is expressed by pachytene spermatocytes and round spermatids
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Memantine inhibits ATP-dependent K+ conductances in dopamine neurons of the rat substantia nigra pars compacta
No full text1-Amino-3,5-dimethyl-adamantane (memantine) is a noncompetitive
N-methyl-D-aspartate (NMDA) receptor antagonist
used in clinical practice to treat neurodegenerative disorders
that could be associated with excitotoxic cell death. Because
memantine reduces the loss of dopamine neurons of
the substantia nigra pars compacta (SNc) in animal models of
Parkinson’s disease, we examined the effects of this drug on
dopamine cells of the SNc. Besides inhibition of NMDA
receptor-mediated currents, memantine (30 and 100 M)
increased the spontaneous firing rate of whole-cell recorded
dopamine neurons in a midbrain slice preparation. Occasionally,
a bursting activity was observed. These effects were
independent from the block of NMDA receptors and were
prevented in neurons dialyzed with a high concentration of
ATP (10 mM). An increase in firing rate was also induced by
the ATP-sensitive potassium (KATP) channel antagonist tolbutamide
(300 M), and this increase occluded further effects
of memantine. In addition, KATP channel-mediated outward
currents, induced by hypoxia, were inhibited by
memantine (30 and 100 M) in the presence of the NMDA
receptor antagonist (5S,10R)-()-5-methyl-10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)
(10 M). An increase in the spontaneous firing rate by memantine
was observed in dopamine neurons recorded with
extracellular planar 8 8 multielectrodes in conditions of
hypoglycemia. These results highlight KATP channels as possible
relevant targets of memantine effects in the brain.
Moreover, in view of a proposed role of KATP conductances
in dopamine neuron degeneration, they suggest another
mechanism of action underlying the protective role of memantine
in Parkinson’s disease
Trace amines depress D2-autoreceptor-mediated responses on midbrain dopaminergic cells.
No full textBackground and purpose: Although trace amines (TAs) are historically considered ‘false neurotransmitters’ on the basis of
their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors,
ligand-gated receptor channels and/or s receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and
b-phenylethylamine (b-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to
the D2 receptor agonist, quinpirole.
Experimental approach: Electrophysiological recordings of D2 receptor-activated G-protein-gated inward rectifier K+ channel
(GIRK) currents were performed on dopaminergic cells from midbrain slices of mice and on Xenopus oocytes expressing D2
receptors and GIRK channels.
Key results: TYR and b-PEA reversibly reduced D2 receptor-activated GIRK currents in a concentration-dependent manner on
SNpc neurones. The inhibitory effect of TAs was still present in transgenic mice with genetically deleted TA1 receptors and they
could not be reproduced by the selective TA1 agonist, o-phenyl-3-iodotyramine (O-PIT). Pretreatment with antagonists of s1
and s2 receptors did not block TA-induced effects. In GTPgS-loaded neurones, the irreversibly-activated GIRK-current was still
reversibly reduced by b-PEA. Moreover, b-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes.
Conclusions and implications: TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from
TA1, s-receptors, D2 receptors or GIRK channels. Although their precise mechanism of action remains to be identified, TAs, by
antagonizing the inhibitory effects of dopamine, may render dopaminergic neurones less sensitive to autoreceptor feedback
inhibition and hence enhance their sensitivity to stimulation
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