Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice

Gioia, Dominic; Alexander, Nancy J.; McCool, Brian A.

doi:10.1523/jneurosci.1785-16.2016

Cited by 18 publications

(41 citation statements)

References 61 publications

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“…This is consistent with previous findings showing greater vesicle recycling in mouse strains expressing lower Munc13-2 levels (Gioia et al, 2016; Gioia and McCool, 2017). More importantly, acute treatment with ethanol significantly slowed the RRP recovery in cells from Munc13-2 knockdown mice (Figure 3C 2 , two-Way ANOVA, main effects of recovery interval, p < 0.001, and ethanol p < 0.01, with Dunnett's post-hoc comparison finding a significant difference at the 10 s interval p < 0.05).…”

Section: Resultssupporting

confidence: 94%

“…Cortical regions like the BLA express both the Munc13-1 and Munc13-2 isoforms while the other isoforms are expressed elsewhere in the brain and throughout the body (Augustin et al, 1999; Gioia et al, 2016). Munc13-1 and Munc13-2 have conserved C-terminal regions but highly divergent N-terminal regions that alter their function within the terminal.…”

Section: Introductionmentioning

confidence: 99%

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Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2

2017

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Chronic exposure to alcohol produces adaptations within the basolateral amygdala (BLA) that are associated with the development of anxiety-like behaviors during withdrawal. In part, these adaptations are mediated by plasticity in glutamatergic synapses occurring through an AMPA receptor mediated form of post-synaptic facilitation in addition to a unique form of presynaptic facilitation. In comparison to the post-synaptic compartment, relatively less is understood about the mechanisms involved in the acute and chronic effects of ethanol in the presynaptic terminal. Previous research has demonstrated that glutamatergic terminals in the mouse BLA are sensitive to ethanol mediated inhibition of synaptic vesicle recycling in a strain-dependent fashion. Importantly, the strain-dependent differences in presynaptic ethanol sensitivity are in accordance with known strain-dependent differences in ethanol/anxiety interactions. In the present study, we have used a short-hairpin RNA to knockdown the expression of the presynaptic Munc13-2 protein in C57BL/6J mice, whose BLA glutamate terminals are normally ethanol-insensitive. We injected this shRNA, or a scrambled control virus, into the medial prefrontal cortex (mPFC) which sends dense projections to the BLA. Accordingly, this knockdown strategy reduces the expression of the Munc13-2 isoform in mPFC terminals within the BLA and alters presynaptic terminal function in C57BL/6J mice in a manner that phenocopies DBA/2J glutamate terminals which are normally ethanol-sensitive. Here, we provide evidence that manipulation of this single protein, Munc13-2, renders C57BL/6J terminals sensitive to ethanol mediated inhibition of synaptic vesicle recycling and post-tetanic potentiation. Furthermore, we found that this ethanol inhibition was dose dependent. Considering the important role of Munc13 proteins in synaptic plasticity, this study potentially identifies a molecular mechanism regulating the acute presynaptic effects of ethanol to the long lasting adaptations in the BLA that occur during chronic ethanol exposure.

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Section: Resultssupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2

2017

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“…The 2.5‐second, 40‐Hz trains of stimuli were used to determine the size of the RRP as well as the synaptic vesicle refilling/recycling rate as described previously (Gioia et al., ; Schneggenburger et al., ). Briefly, response amplitudes were summed across the stimulation trained and used to construct cumulative amplitude plots for each cell during baseline and EtOH exposure.…”

Section: Methodsmentioning

confidence: 99%

Strain‐Dependent Effects of Acute Alcohol on Synaptic Vesicle Recycling and Post‐Tetanic Potentiation in Medial Glutamate Inputs to the Mouse Basolateral Amygdala

Gioia

McCool

2017

Alcoholism Clin & Exp Res

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Background Inbred mouse strains are differentially sensitive to the acute effects of ethanol and are useful tools for examining how unique genomes differentially affect alcohol-related behaviors and physiology. DBA/2J mice have been shown to be sensitive to the acute anxiolytic effects of alcohol as well as the anxiogenic effects of withdrawal from chronic alcohol exposure, while B6 mice are resistant to both. Considering that the basolateral amygdala is an important brain region for the acute and chronic effects of ethanol on fear and anxiety related behaviors, we hypothesized that there would be strain-dependent differences in the acute effects of ethanol in BLA slices. Methods We utilized patch clamp electrophysiology in BLA coronal slices from four inbred mouse strains (A/J, BALBcJ, C57BL/6J and DBA2/J) to examine how genetic background influences acute ethanol effects on synaptic vesicle recycling and post-tetanic potentiation in response to low (2 Hz) and high (40 Hz) frequency stimulation. Results We found that ethanol inhibited synaptic vesicle recycling in a strain- and stimulation frequency-dependent manner. Vesicle recycling in DBA/2J and BALBcJ cells was inhibited by acute ethanol during both low and high frequency stimulation while recycling measured from AJ cells was sensitive only during high frequency stimulation. Recycling at C57BL/6J synapses was insensitive to ethanol regardless of stimulation frequency. We additionally found that cells from DBA/2J and BALBcJ mice were sensitive to ethanol-mediated inhibition of post-tetanic potentiation. Conclusions Acute ethanol application inhibited vesicle recycling and post-tetanic potentiation at glutamatergic synapses in both a strain- and frequency-dependent fashion. Several presynaptic proteins that contribute to synaptic vesicle priming in addition to post-tetanic potentiation have been implicated in alcohol-related behaviors, including Munc13, Munc18, and RIM proteins, making them potential candidates for the molecular mechanism controlling these effects.

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“…; Gioia et al . ). The RRP size of l ‐AP4 (500 μ m , 10 min) treated slices stimulated at 40 Hz for 2.5 s increased from 1150.2 (±268.3) to 1589.7 (±309.9) pA, P = 0.0035: Fig.…”

Section: Resultsmentioning

confidence: 97%

“…In addition, Munc13‐2 proteins have been associated with the potentiation of synaptic transmission at several synapses (Gioia et al . ; Kawabe et al . ) in a PLC dependent manner (Rosenmund et al .…”

Section: Discussionmentioning

confidence: 99%

Bidirectional modulation of glutamatergic synaptic transmission by metabotropic glutamate type 7 receptors at Schaffer collateral–CA1 hippocampal synapses

Martín

Ferrero

Collado-Alsina

et al. 2018

The Journal of Physiology

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Neurotransmitter release is driven by Ca influx at synaptic boutons that acts on synaptic vesicles ready to undergo exocytosis. Neurotransmitter release is inhibited when metabotropic glutamate type 7 (mGlu ) receptors provoke a reduction in Ca influx, although the reduced release from synapses lacking this receptor suggests that they may also prime synaptic vesicles for release. These mGlu receptors activate phospholipase C (PLC) and generate inositol trisphosphate, which in turn releases Ca from intracellular stores and produces diacylglycerol (DAG), an activator of proteins containing DAG-binding domains such as Munc13 and protein kinase C (PKC). However, the full effects of mGlu receptor signalling on synaptic transmission are unclear. We found that prolonged activation of mGlu receptors with the agonist l-AP4 first reduces and then enhances the amplitude of EPSCs, a presynaptic effect that changes the frequency but not the amplitude of the mEPSCs and the paired pulse ratio. Pertussis toxin blocks the inhibitory response, while the PLC inhibitor U73122, and the inhibitor of DAG binding calphostin C, prevent receptor mediated potentiation. Moreover, this DAG-dependent potentiation of the release machinery brings more synaptic vesicles closer to the active zone plasma membrane in a Munc13-2- and RIM1α-dependent manner. Electrically evoked release of glutamate that activates mGlu receptors also bidirectionally modulates synaptic transmission. In these conditions, potentiation now occurs rapidly and it overcomes any inhibition, such that potentiation prevails unless it is suppressed with the PLC inhibitor U73122.

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Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice

Cited by 18 publications

References 61 publications

Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2

Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2

Strain‐Dependent Effects of Acute Alcohol on Synaptic Vesicle Recycling and Post‐Tetanic Potentiation in Medial Glutamate Inputs to the Mouse Basolateral Amygdala

Bidirectional modulation of glutamatergic synaptic transmission by metabotropic glutamate type 7 receptors at Schaffer collateral–CA1 hippocampal synapses

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