Silencing neurotransmission with membrane-tethered toxins

Auer, Sebastian; Stürzebecher, Annika; Jüttner, René; Santos-Torres, Julio; Hanack, Christina; Frahm, Silke; Liehl, Beate; Ibañez–Tallon, Inés

doi:10.1038/nmeth.1425

Cited by 50 publications

(59 citation statements)

References 35 publications

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“…Briefly, this manipulation involves viral expression of flexed (Creinducible inversion) tetanus toxin in PVT neurons and viral expression of cre in NAc shell neurons, which is fused with wheat germ agglutinin (WGA) so it is retrogradely transsynaptically transported, such that tetanus toxin is only activated and expressed in infected PVT neurons that project to infected NAc neurons. This technique has been extensively characterized (Braz et al, 2002;Auer et al, 2010;Xu and Sudhof, 2013;Christoffel et al, 2015) and has been reliably used to block synaptic transmission within the PVTto-NAc pathway (Christoffel et al, 2015). Our results show that disrupting synaptic transmission of PVT neurons that project to the NAc shell substantially decreased the acquisition of cocaine self-administration (0.75 mg/kg/infusion; 2 h/d × 5 d after 1 overnight training).…”

Section: Introductionmentioning

confidence: 78%

“…Thus only PVT neurons that projected to the NAc shell expressed TetTox, which in turn disrupted the synaptic release of these neurons. This technique has been characterized (Braz et al, 2002;Auer et al, 2010;Xu and Sudhof, 2013;Christoffel et al, 2015) and has been used to block synaptic transmission within the PVTto-NAc pathway (Christoffel et al, 2015). Four weeks after intra-NAc injection of WGA-cre AAVs and intra-PVT injection of Flx-TetTox AAV, a substantial number of EGFP-expressing neurons were detected in the PVT, indicating expression of TetTox within these neurons (Figure 1c).…”

Section: Synaptic Transmission In Pvt Neurons That Project To Nacmentioning

confidence: 99%

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Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Neumann

Wang

Yan

et al. 2016

Neuropsychopharmacol

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Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine selfadministration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1 d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short-and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.

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Section: Introductionmentioning

confidence: 78%

Section: Synaptic Transmission In Pvt Neurons That Project To Nacmentioning

confidence: 99%

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Neumann

Wang

Yan

et al. 2016

Neuropsychopharmacol

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“…Given our demonstration that the action of oxytocin on OxtrCre neurons is to stimulate their activity, and recent studies showing that manipulation of the general balance of excitation and inhibition in the mPFC alters social behavior (Yizhar et al, 2011), we next tested directly the impact of OxtrCre neurons in the mPFC in mouse social interactions. To do so, we chose the viral mediated tethered toxin (t-toxin) strategy for chronic inhibition of neurotransmission (Auer et al, 2010; Warner-Schmidt et al, 2012) in mPFC OxtrCre interneurons, and the three chamber mouse social interaction test (Moy et al, 2004). Adult OxtrCre mice were injected stereotactically at four sites in the mPFC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oxytocin Modulates Female Sociosexual Behavior through a Specific Class of Prefrontal Cortical Interneurons

Nakajima

Görlich

Heintz

2014

Cell

240

214

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SUMMARY Human imaging studies have revealed that intranasal administration of the “prosocial” hormone oxytocin (OT) activates the frontal cortex, and that this action of OT correlates with enhanced brain function in autism. Here we report the discovery of a population of somatostatin (Sst) positive, regular spiking interneurons that express the oxytocin receptor (OxtrINs). Silencing of OxtrINs in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice specifically during the sexually receptive phase of the estrous cycle. This sociosexual deficit was also present in mice in which the Oxtr gene was conditionally deleted from the mPFC, and in control mice infused with an Oxtr antagonist. Our data demonstrate a gender, cell type and state specific role for OT/Oxtr signaling in the mPFC, and identify a latent cortical circuit element that may modulate other complex social behaviors in response to OT.

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“…To definitively identify accumbal ChAT neurons as regulators of depression-like behaviors and to determine how the activity of these neurons is involved in the behavioral outputs, we silenced neurotransmission in these cells by using virus-mediated delivery of two membrane-tethered toxins (ttoxins) against calcium voltage-gated channels. This approach has been used in other cell types and has been shown to effectively silence neurotransmission in cells expressing these t-toxins (16). Mice expressing CRE recombinase under the ChAT bac promoter were infected with the CRE-dependent AAV-t-toxins MPE and APC or with control AAV-PE virus.…”

Section: Silencing Neurotransmission In Cholinergic Interneurons Inducesmentioning

confidence: 99%

“…T-toxin expression cassettes (named MPE and APC) contained the sequences encoding the MVIIA conotoxin (from Conus magus) fused to the PDGF-receptor transmembrane domain followed by EGFP (MPE), or the AgaIVA agatoxin (from Agenelopsis aperta), followed by the TM domain and mCherry (APC). The no-toxin control contains the transmembrane domain of the PDGF receptor and EGFP (PE) (16). Double floxed AAV constructs were generated by insertion of the inverted t-toxin expression cassettes MPE or APC or the no-toxin control PE between double lox 2722 and lox P incompatible sites (DFI).…”

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confidence: 99%

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Warner-Schmidt¹,

Schmidt

Marshall³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

152

159

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A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.he nucleus accumbens (NAC) has been identified as a critical site in the neuronal circuits controlling reward responses, motivation, and mood (1-3). For example, in major depressive disorder (MDD): (i) NAC activity is reduced in response to positive stimuli (4) and (ii) MDD symptoms can be reversed by deep brain stimulation in the NAC (5, 6). Although these regional studies implicate the NAC, the cell type(s) responsible for the pathophysiology remain to be elucidated. In the case of MDD, it is crucial that we determine which neuronal cell types regulate depressive-like behaviors to eventually develop highly targeted antidepressants that could be both faster acting and have fewer off-site effects. MDD is a debilitating psychiatric condition characterized by anhedonia (defined as a loss of interest in pleasurable things), loss of motivation, negative affect, behavioral despair, and changes in cognition and basic drives such as eating and sleeping. Despite its complexity, central features of the disease, such as anhedonia and behavioral despair, can be modeled in rodents to probe the underlying neuronal circuitry.The serotonin receptor (5HTR) interacting protein p11 is a small intracellular protein that regulates the localization of certain 5HTRs, including 5HTR1B and 5HTR4 (7,8), at the cellular surface. Constitutive p11 knockout (KO) mice show both anhedonia (e.g., reduced sucrose preference) and increased behavioral despair (e.g., increased immobility) (7-9). Recently, we identified the NAC as a key brain region in which loss of p11 induces depression-like behaviors (9). The NAC is composed of several different cell types (10). Approximately 95% of the neurons in this region are medium spiny neurons (MSNs), the projection neurons of the NAC. The cholinergic interneurons have a characteristically large soma and make up less than 1% of the neurons in the striatum (10). Cholinergic interneurons primarily target MSNs via muscarinic and nicotinic acetylcholine receptors, a...

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Silencing neurotransmission with membrane-tethered toxins

Cited by 50 publications

References 35 publications

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Oxytocin Modulates Female Sociosexual Behavior through a Specific Class of Prefrontal Cortical Interneurons

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

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