Abstract
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.
Highlights
Alcohol use disorders (AUDs) are frequently comorbid with anxiety related disorders including generalized anxiety disorder, panic disorder, and post-traumatic stress disorder (Regier et al, 1990)
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 basolateral amygdala (BLA) that occur during chronic ethanol exposure
We have previously shown that chronic ethanol exposure induces a presynaptic form of plasticity in the medial glutamatergic inputs to the BLA (Christian et al, 2013) and that microinjection of glutamatergic antagonists into the BLA prevents the expression of withdrawal related anxiety (Läck et al, 2007)
Summary
Alcohol use disorders (AUDs) are frequently comorbid with anxiety related disorders including generalized anxiety disorder, panic disorder, and post-traumatic stress disorder (Regier et al, 1990). In order to provide effective treatments for people with comorbid anxiety and AUDs, it will be important to further understand the mechanisms involved in alcohol-induced adaptations in anxiety related brain regions. We have previously shown that chronic ethanol exposure induces a presynaptic form of plasticity in the medial glutamatergic inputs to the BLA (Christian et al, 2013) and that microinjection of glutamatergic antagonists into the BLA prevents the expression of withdrawal related anxiety (Läck et al, 2007). Together, these studies suggested that ethanol related plasticity in presynaptic medial inputs to the BLA may drive the expression of anxiety-like behavior during withdrawal. The mechanisms involved in this plasticity are currently unknown, they may provide novel therapeutic targets for people with comorbid alcohol use and anxiety disorders
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