mercoledì 23 aprile 2014

Apprendimento e memoria: ecco le novità molecolari

di Alberto Carrara, LC
Coordinatore del Gruppo di Neurobioetica (GdN)

Una nuova ricerca condotta da un gruppo di scienziati del TSRI, il Florida campus of The Scripps Research Institute (USA), ha individuato nuovi complessi proteici coinvolti nei meccanismi cerebrali di apprendimento e memorizzazione.

La ricerca, intitolata RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling, pubblicata online lo scorso 22 aprile su eLife 2014;3:e02053 (Published April 22, 2014), mette in luce il ruolo chiave svolto dalla proteina denominata RGS7 nel processo di memorizzazione, come afferma lo stesso professor Kirill Martemyanov, docente associato del TSRI che ha guidato la ricerca.


La conoscenza di questo nuovo importante fattore proteico offre una “finestra” terapeutica innovativa. Potenziando l’attivazione (e/o la trascrizione e l’espressione) del gene per la codifica di RGS7, si potrebbero ipotizzare nuove frontiere terapeutiche per patologie neurodegenerative coinvolgenti deficit mnesici importanti.

Certamente, in ambito di riflessione neurobioetica, quando si parla di “potenziamento” o enhancement, sono doverose le opportune cautele. La terapeuticità del “potenziamento” deve essere valutata da medici ed esperti neurologi e neuroscienziati, insieme a professionisti del settore della ricerca neurobioetica, al fine di prevenire futili applicazioni in chiave di “potenziamento” eugenetico di specie.

Il gruppo di ricerca che ha pubblicato quest’importante lavoro sulla rivista eLife promossa dal Howard Hughes Medical Institute, dalla Max Planck Society e dal Wellcome Trust, guarda con speranza alla RGS7 espressa a livello di quella struttura cerebrale denominata ippocampo, una piccola porzione del nostro cervello che aiuta in maniera determinante a convertire le memorie a breve termine in memorie a lungo termine.

Inoltre, gli scienziati hanno individuato un’altra proteina, la R7BP, che, insieme alla
RGS7, regolerebbe la cascata del segnale (trasduzione del segnale) che coinvolge il neurotrasmettitore GABA, via critica per lo sviluppo cognitive umano.

Come è noto, il GABA, legandosi ai sui recettori specifici, i GABAb recettori, ingenera l’apertura di canali ionici inibitori, denominati GIRKs, posti sulla membrana cellulare dei neuroni. Quest’azione inibisce la cellula nervosa, cioè rende più difficile al neurone la trasmissione del potenziale elettrochimico.

L’intero articolo si può leggere e scaricare gratuitamente QUI.

Ne riporto l’abstract e l’introduzione in lingua originale.

Abstract
In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation.

Introduction
Signaling through G protein-coupled receptors for the inhibitory neurotransmitter GABA (GABABR) has been recognized to play key roles in mood, nociception, memory, reward, and movement (Bowery, 2006; Padgett and Slesinger, 2010). In the hippocampus, activation of postsynaptic GABABR on pyramidal neurons produces slow inhibitory postsynaptic currents (sIPSCs), which counteract the excitatory influence of ionotropic glutamate receptors to shape neuronal output (Ulrich and Bettler, 2007; Luscher and Slesinger, 2010). As a result, GABABR signaling profoundly affects hippocampal synaptic plasticity and has marked effects on memory formation (Davies et al., 1991; Wagner and Alger, 1995; Schuler et al., 2001).
A large share of the postsynaptic inhibitory effect of GABABR stimulation in the hippocampus is mediated by activation G protein-gated inwardly-rectifying K+ (GIRK/Kir3) channels, which inhibit neuronal excitability via hyperpolarizing K+ efflux (Luscher and Slesinger, 2010). In the hippocampus, GIRK channels are predominantly formed by GIRK1 and GIRK2 subunits, which co-localize and may interact directly with GABABR protomers (Koyrakh et al., 2005;Fajardo-Serrano et al., 2013). Activation of GABABR releases G protein βγ subunits, which bind to GIRK channels and increase channel gating (Padgett and Slesinger, 2010). Blockade of GABABR or GIRK channels by either pharmacological manipulations or genetic knockout ablates the slow IPSC, and blunts a form of hippocampal synaptic plasticity known as depotentiation (Luscher et al., 1997; Chung et al., 2009). Conversely, enhanced GABABR-GIRK signaling seen in a mouse model of Down syndrome disrupts both excitatory and inhibitory synaptic plasticity, and is linked to cognitive impairment (Kleschevnikov et al., 2004; Cramer et al., 2010; Cooper et al., 2012).
GABABR-GIRK signaling is negatively modulated by the Regulators of G protein Signaling (RGS) proteins, which accelerate G protein inactivation (Hollinger and Hepler, 2002; Padgett and Slesinger, 2010). Among more than 30 RGS genes found in mammalian genomes, the R7 family of RGS proteins (R7 RGS) stands out for its prominent roles in a range of fundamental neuronal processes, from vision to motor control to reward-related behavior (Anderson et al., 2009). The four members of this group (RGS6, RGS7, RGS9 and RGS11) form heterotrimers with two subunits (Gβ5 and R7BP), and these interactions regulate the localization and/or expression of the complexes (Anderson et al., 2009; Jayaraman et al., 2009).
Previous studies have shown that Gβ5 serves as a central scaffold that bridges the catalytic (RGS) and targeting (R7BP) subunits and ensures the stability of R7 RGS protein (Cheever et al., 2008; Sandiford et al., 2010;Masuho et al., 2011). Elimination of Gβ5 also resulted in dramatic slowing of GIRK channel deactivation kinetics, prolongation of synaptically-evoked slow IPSCs in hippocampal pyramidal neurons, and increased behavioral sensitivity to GABABR stimulation (Xie et al., 2010). However, the identity of the RGS isoform that modulates GABABR-GIRK signaling in hippocampus, as well as the relative impact of the R7BP subunit, are unknown. Furthermore, the relevance of RGS-dependent modulation of GIRK-dependent signaling to hippocampal circuit function, plasticity, and behavior remain unclear.
In this study, we examined the importance of RGS and R7BP subunits to hippocampal physiology and hippocampal-dependent behavior. We report that ablation of Rgs7 results in alterations of GABABR-GIRK signaling, disrupts synaptic plasticity in the hippocampus, and impairs contextual learning and memory. Moreover, the function of the RGS7/Gβ5 complex is fine-tuned by R7BP, which sets the sensitivity range of GABABR-GIRK signaling.

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