Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice

Liu, Zhipeng; He, Qi; Pan, Han‐Qing; Xü, Xinsheng; Chen, Wen‐Bing; He, Ye; Zhou, Jian‐Liang; Zhang, Wenhua; Zhang, Junyu; Ying, Xiaoping; Han, Ren-wen; Li, Baoming; Gao, Tianming; Pan, Bing‐Xing

doi:10.1016/j.biopsych.2016.06.022

Cited by 38 publications

(19 citation statements)

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“…Ethanol is thought to produce anxiolytic effects by increasing tonic inhibition synergistically by both directly targeting extrasynaptic GABA A Rs and by enhancing Golgi cell firing, which raises GABA levels in the cerebellar input layer (Richardson and Rossi, 2017). Previous studies investigating GABA A Rs and anxiety focused on brain regions classically associated with fear, such as the amygdala, hypothalamus and hippocampus (Lee et al, 2014;Liu et al, 2017;Maguire et al, 2005). Our study establishes the importance of GABA A Rs in the input layer of the cerebellum in regulating anxiety.…”

Section: Increased Anxiety-like Behavior In Cb  Ko Micesupporting

confidence: 68%

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Rudolph

Guo

Pashkovski

et al. 2019

Preprint

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GABAA receptors containing the GABAA subunit (GABAARs) are involved in many physiological and pathophysiological processes, such as sleep, pain, stress, anxiety-related behaviors, and postpartum depression. These extrasynaptically located, high affinity and slowly desensitizing receptors mediate tonic inhibition throughout the brain, including in granule cells (GCs) of the cerebellar input layer. However, the extent to which GABAARs control the excitability of the cerebellar input layer and ultimately regulate behavior is unknown.We therefore deleted GABAA subunits specifically from GCs and determined the behavioral consequences in mice. Deletion reduced tonic inhibition and increased input layer excitability, but remarkably, did not affect either locomotion or motor learning. Unexpectedly, GABAA deletion heightened anxiety-like behaviors, and caused female-specific alterations in social and maternal behavior. Our findings establish that the cerebellar input layer is critical for regulating diverse behaviors that are relevant to psychiatric and neurodevelopmental disorders but were previously not associated with the cerebellum.

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Section: Increased Anxiety-like Behavior In Cb  Ko Micesupporting

confidence: 68%

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Rudolph

Guo

Pashkovski

et al. 2019

Preprint

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“…Neogenin was detected in the brain (van den Heuvel et al, 2013;; however, its exact expression pattern in adult brain is not clear due to the lack of reliable antibodies for immunohistochemical study (data not shown). To this end, we used Neogenin-lacZ mice where the LacZ gene was inserted in the intron of the Neogenin gene (Lee et al, 2010). Under the control of the endogenous promoter, ␤-gal expression is thought to faithfully indicate where Neogenin is expressed .…”

Section: Enriched Expression Of Neogenin In Excitatory Neurons In Blamentioning

confidence: 99%

“…Neogenin, a Type I transmembrane protein of the DCC (deleted in colorectal cancer) family, was identified as a receptor for the axon guidance cue netrin-1 as well as repulsive guidance molecules (Vielmetter et al, 1994;Rajagopalan et al, 2004;De Vries and Cooper, 2008;Xu et al, 2014). Recent data suggest that Neogenin has diverse functions in various organs, such as endochondral bone formation , neural tube formation (Kee et al, 2008), digit patterning (Hong et al, 2012), ion metabolism (Kuns-Hashimoto et al, 2008;Lee et al, 2010), and muscle differentiation (Kang et al, 2004). Neogenin is expressed in embryonic and adult neural stem cells (Fitzgerald et al, 2007;van den Heuvel et al, 2013) and has been implicated in adult neurogenesis (O'Leary et al, 2015;.…”

Section: Introductionmentioning

confidence: 99%

Neogenin in Amygdala for Neuronal Activity and Information Processing

et al. 2018

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Fear learning and memory are vital for livings to survive, dysfunctions in which have been implicated in various neuropsychiatric disorders. Appropriate neuronal activation in amygdala is critical for fear memory. However, the underlying regulatory mechanisms are not well understood. Here we report that Neogenin, a DCC (deleted in colorectal cancer) family receptor, which plays important roles in axon navigation and adult neurogenesis, is enriched in excitatory neurons in BLA (Basolateral amygdala). Fear memory is impaired in male mutant mice. The number of cFos neurons in response to tone-cued fear training was reduced in mutant mice, indicating aberrant neuronal activation in the absence of Neogenin. Electrophysiological studies show that mutation reduced the cortical afferent input to BLA pyramidal neurons and compromised both induction and maintenance of Long-Term Potentiation evoked by stimulating cortical afferent, suggesting a role of Neogenin in synaptic plasticity. Concomitantly, there was a reduction in spine density and in frequency of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents, suggesting a role of Neogenin in forming excitatory synapses. Finally, ablating in the BLA in adult male mice impaired fear memory likely by reducing mEPSC frequency in BLA excitatory neurons. These results reveal an unrecognized function of Neogenin in amygdala for information processing by promoting and maintaining neurotransmission and synaptic plasticity and provide insight into molecular mechanisms of neuronal activation in amygdala. Appropriate neuronal activation in amygdala is critical for information processing. However, the underlying regulatory mechanisms are not well understood. Neogenin is known to regulate axon navigation and adult neurogenesis. Here we show that it is critical for neurotransmission and synaptic plasticity in the amygdala and thus fear memory by using a combination of genetic, electrophysiological, behavioral techniques. Our studies identify a novel function of Neogenin and provide insight into molecular mechanisms of neuronal activation in amygdala for fear processing.

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“…Tonic inhibition, which is mediated by extrasynaptically located GABA A Rs, has been extensively observed in many brain regions including cerebellum, hippocampus, amygdala, and neocortex (Brickley and Mody, 2012). Accumulating evidence indicates that the tonic inhibition in amygdala plays a key role in the inhibitory control of amygdala activity (Marowsky et al, 2012;Martin et al, 2014;Liu et al, 2017;Meis et al, 2018). Surprisingly, our results showed that the expression of tonic inhibition in BLA PNs varied drastically with the presence or absence of Thy1, and the tonic GABA A R currents in Thy1+ neurons were far lower than those in Thy1-PNs under normal physiological conditions (control mice).…”

Section: Discussionmentioning

confidence: 99%

Chronic Stress Oppositely Regulates Tonic Inhibition in Thy1-Expressing and Non-expressing Neurons in Amygdala

et al. 2020

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Chronic or prolonged exposure to stress ranks among the most important socioenvironmental factors contributing to the development of neuropsychiatric diseases, a process generally associated with loss of inhibitory tone in amygdala. Recent studies have identified distinct neuronal circuits within the basolateral amygdala (BLA) engaged in different emotional processes. However, the potential circuit involved in stress-induced dysregulation of inhibitory tones in BLA remains elusive. Here, a transgenic mouse model expressing yellow fluorescent protein under control of the Thy1 promoter was used to differentiate subpopulations of projection neurons (PNs) within the BLA. We observed that the tonic inhibition in amygdala neurons expressing and not expressing Thy1 (Thy1+/−) was oppositely regulated by chronic social defeat stress (CSDS). In unstressed control mice, the tonic inhibitory currents were significantly stronger in Thy1-PNs than their Thy1+ counterparts. CSDS markedly reduced the currents in Thy1-projection neurons (PNs), but increased that in Thy1+ ones. By contrast, CSDS failed to affect both the phasic A-type γ-aminobutyric acid receptor (GABA A R) currents and GABA B R currents in these two PN populations. Moreover, chronic corticosterone administration was sufficient to mimic the effect of CSDS on the tonic inhibition of Thy1+ and Thy1-PNs. As a consequence, the suppression of tonic GABA A R currents on the excitability of Thy1-PNs was weakened by CSDS, but enhanced in Thy1+ PNs. The differential regulation of chronic stress on the tonic inhibition in Thy1+ and Thy1-neurons may orchestrate cell-specific adaptation of amygdala neurons to chronic stress.

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Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice

Cited by 38 publications

References 50 publications

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Neogenin in Amygdala for Neuronal Activity and Information Processing

Chronic Stress Oppositely Regulates Tonic Inhibition in Thy1-Expressing and Non-expressing Neurons in Amygdala

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Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice

Cited by 38 publications

References 50 publications

Cerebellum-specific deletion of the GABAAreceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Cerebellum-specific deletion of the GABAAreceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Neogenin in Amygdala for Neuronal Activity and Information Processing

Chronic Stress Oppositely Regulates Tonic Inhibition in Thy1-Expressing and Non-expressing Neurons in Amygdala

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Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance