Distinct Mechanisms of Ethanol Potentiation of Local and Paracapsular GABAergic Synapses in the Rat Basolateral Amygdala
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. Journal of Pharmacology and Experimental Therapeutics
(Impact Factor: 3.97).
02/2008; 324(1):251-60. DOI: 10.1124/jpet.107.128728
Converging lines of behavioral and pharmacological evidence suggest that GABAergic synapses in the basolateral amygdala (BLA) may play an integral role in mediating the anxiolytic effects of ethanol (EtOH). Since anxiety is thought to play an important role in the development of, and relapse to, alcoholism, elucidating the mechanisms through which EtOH modulates GABAergic synaptic transmission in the BLA may be fundamental in understanding the etiology of this disease. A recent study in mice has shown that principal cells within the BLA receive inhibitory input from two distinct types of GABAergic interneurons: a loosely distributed population of local interneurons and a dense network of paracapsular (pcs) GABAergic cells clustered along the external capsule border. Here, we sought to confirm the presence of these two populations of GABAergic synapses in the rat BLA and evaluate their ethanol sensitivity. Our results suggest that rat BLA pyramidal cells receive distinct inhibitory input from local and pcs interneurons and that EtOH potentiates both populations of synapses, albeit via distinct mechanisms. EtOH enhancement of local inhibitory postsynaptic currents (IPSCs) was associated with a significant decrease in paired-pulse ratio (PPR) and was significantly potentiated by the GABA(B) receptor antagonist SCH 50911 [(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid], consistent with a facilitation of GABA release from presynaptic terminals. Conversely, EtOH enhancement of pcs IPSCs did not alter PPR and was not enhanced by SCH 50911 but was inhibited by blockade of noradrenergic receptors. Collectively, these data reveal that EtOH can potentiate GABAergic inhibitory synaptic transmission in the rat BLA through at least two distinct pathways.
Available from: Yuko Sekino
- "In the present study, the contribution of the lateral intercalated clusters located in the EClat was smaller than that of the m-ITC, although the pathway from the lateral intercalated clusters to the BLA has been shown anatomically and electrophysiologically  . Because the direction of the stimulus electrode used in the present study was from the EClat to the ECmed, resulting in the selective stimulation of the ECmed, the contribution of the lateral intercalated clusters to the inhibitory response in vivo cannot be excluded. "
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ABSTRACT: The lateral amygdala nucleus (La) is known as a gateway for emotional learning that interfaces sensory inputs from the cortex and the thalamus. In the La, inhibitory GABAergic inputs control the strength of sensory inputs and interfere with the initial step of the acquisition of fear memory. In the present study, we investigated the spatial and temporal patterns of the inhibitory responses in mouse La using voltage-sensitive dye imaging. Stimulating the external capsule (EC) induced large and long-lasting hyperpolarizing signals in the La. We focused on these hyperpolarizing signals, revealing the origins of the inhibitory inputs by means of surgical cuts on the possible afferent pathways with four patterns. Isolating the medial branch of EC (ECmed), but not the lateral branch of EC (EClat), from the La strongly suppressed the induction of the hyperpolarization. Interestingly, isolating the ECmed from the caudate putamen did not suppress the hyperpolarization, while the surgical cut of the ECmed fiber tract moderately suppressed it. Glutamatergic antagonists completely suppressed the hyperpolarizing signals induced by the stimulation of EC. When directly stimulating the dorsal, middle or ventral part of the ECmed fiber tract in the presence of glutamatergic antagonists, only the stimulation in the middle part of the ECmed caused hyperpolarization. These data indicate that the GABAergic neurons in the medial intercalated cluster (m-ITC), which receive glutamatergic excitatory input from the ECmed fiber tract, send inhibitory afferents to the La. This pathway might have inhibitory effects on the acquisition of fear memory.
Copyright © 2015. Published by Elsevier Ireland Ltd.
Neuroscience Letters 01/2015; 590. DOI:10.1016/j.neulet.2015.01.079 · 2.03 Impact Factor
- "Heart-rescued ErbB4 knockout mice have been described previously (Tidcombe et al, 2003). GAD-GFP mice have been used to provide morphological and electrophysiological evidence of GABAergic interneurons for which the synapse project onto glutamatergic pyramidal neurons (Chieng et al, 2011; Marowsky et al, 2005; Silberman et al, 2008; Tamamaki et al, 2003). For more details on the generation and expression properties of ErbB4-Cre-ERT2 mice, please go to http:// transgenicmouse.alleninstitute.org. "
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ABSTRACT: Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4 which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA) was expressed in GABAergic neurons. Endogenous NRG1-ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1-ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia.Neuropsychopharmacology accepted article preview online, 13 October 2014. doi:10.1038/npp.2014.274.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2014; 40(4). DOI:10.1038/npp.2014.274 · 7.05 Impact Factor
Available from: Jeff L Weiner
- "The second pathway arises from a distinct class of GABAergic interneurons, termed lateral paracapsular cells (LPCS), which cluster along the border between the BLA and the external capsule and are thought to provide cortical feed-forward inhibition within the BLA (Marowsky et al, 2005; Silberman et al, 2008). Importantly, recent data suggest that b3 mRNA is expressed in the amygdala (Claustre et al, 2008) and that LPCS-mediated synaptic inhibition may be enhanced by NE (Silberman et al, 2008). Therefore, in this study, we used electrophysiological and behavioral approaches to investigate the hypothesis that activation of LPCS-mediated inhibition in the BLA may contribute to the anxiolytic effects of b3-AR agonists. "
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ABSTRACT: Norepinephrine (NE) is known to play an integral role in the neurobiological response to stress. Exposure to stressful stimuli increases NE levels in brain regions that regulate stress and anxiety, like the basolateral amygdala (BLA). NE is thought to increase excitability in these areas through α- and Β-adrenoceptors (ARs), leading to increased anxiety. Surprisingly, recent studies have shown that systemic Β3-AR agonist administration decreases anxiety-like behaviors, suggesting that Β3-ARs may inhibit excitability in anxiety-related brain regions. Therefore, in this study we integrated electrophysiological and behavioral approaches to test the hypothesis that the anxiolytic effects of Β3-AR agonists may be mediated by an increase in BLA GABAergic inhibition. We examined the effect of a selective Β3-AR agonist, BRL37344 (BRL), on GABAergic synapses arising from local circuit interneurons and inhibitory synapses originating from a recently described population of cells called lateral paracapsular (LPCS) interneurons. Surprisingly, BRL selectively enhanced LPCS-evoked inhibitory postsynaptic currents (eIPSCs) with no effect on local GABAergic inhibition. BRL also had no effect on glutamatergic synaptic excitation within the BLA. BRL potentiation of LPCS eIPSCs was blocked by the selective Β3-AR antagonist, SR59230A, or by intracellular dialysis of Rp-CAMPS (cAMP-dependent protein kinase inhibitor), and this enhancement was not associated with any changes in spontaneous IPSCs or LPCS paired-pulse ratio. BRL also increased the amplitude of unitary LPCS IPSCs (uIPSCs) with no effect on uIPSC failure rate. Finally, bilateral BLA microinjection of BRL reduced anxiety-like behaviors in an open-field assay and the elevated plus-maze. Collectively, these data suggest that Β3-AR activation selectively enhances LPCS, but not local, BLA GABAergic synapses, and that increases in LPCS-mediated inhibition may contribute to the anxiolytic profile of Β3-AR agonists.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2010; 35(9):1886-96. DOI:10.1038/npp.2010.59 · 7.05 Impact Factor
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