GAD2 Expression Defines a Class of Excitatory Lateral Habenula Neurons in Mice that Project to the Raphe and Pontine Tegmentum

Quina, Lely A.; Walker, Andrew W.; Morton, Glenn; Han, Victor Z.; Turner, Eric E.

doi:10.1523/eneuro.0527-19.2020

Cited by 30 publications

(34 citation statements)

References 54 publications

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“…GAD65, encoded by the Gad2 gene, is a Glutamate decarboxylase 2 enzyme which catalyzes production of gamma-aminobutyric acid (GABA) from L-glutamic acid. These mice have been used to examine the role of GABA and GAD65 in the brain where GAD65Cre-driven reporter expression was specific for GABA-expressing neurons with no mis-expression in other neuron types (Dergacheva et al, 2020;Quina et al, 2020;Whyland et al, 2020). This specific labeling is consistent with the observation that GABAergic neurons turn on Gad2 as they differentiate (Westmoreland et al, 2001).…”

Section: Discussionsupporting

confidence: 56%

GAD65Cre drives reporter expression in multiple taste cell types

Larson

Vandenbeuch

Anderson

et al. 2021

Preprint

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In taste buds, Type I cells represent the majority of cells (50-60%) and primarily have a glial-like function in taste buds. However, recent studies suggest that they have additional sensory and signaling functions including amiloride-sensitive salt transduction, oxytocin modulation of taste, and substance P mediated GABA release. Nonetheless, the overall function of Type I cells in transduction and signaling remains unclear, primarily because of the lack of a reliable reporter for this cell type. GAD65 expression is specific to Type I taste cells and GAD65 has been used as a Cre driver to study Type I cells in salt taste transduction. To test the specificity of transgene-driven expression, we crossed GAD65Cre mice with floxed tdTomato and Channelrhodopsin (ChR2) lines and examined the progeny with immunochemistry, chorda tympani recording, and calcium imaging. We report that while many tdTomato+ taste cells express NTPDase2, a specific marker of Type I cells, we see expression of tdTomato in both Gustducin and SNAP25 positive taste cells. We also see ChR2 in cells just outside the fungiform taste buds. Chorda tympani recordings in the GAD65Cre/ChR2 mice show large responses to blue light, larger than any response to standard taste stimuli. Further, several isolated tdTomato positive taste cells responded to KCl depolarization with increases in intracellular calcium, indicating the presence of voltage-gated calcium channels. Taken together, these data suggest that GAD65Cre mice drive expression in multiple taste cell types and thus cannot be considered a reliable reporter of Type I cell function.

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Section: Discussionsupporting

confidence: 56%

GAD65Cre drives reporter expression in multiple taste cell types

Larson

Vandenbeuch

Anderson

et al. 2021

Preprint

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“…These neurons are likely distinct from the aforementioned population of GAD-2 expressing neurons in that they are confined to the lateral LHb and also express the vesicular GABA transporter (VGAT; Webster et al, 2020), another well-known marker of inhibitory neurons, but largely do not express GAD-2 (Nakamura et al, 2021). Note however that the expression patterns of GABAergic markers within the LHb appears to differ between mice and rats (Quina et al, 2020), with VGAT expression in rats observed in the medial LHb and GAD-2 expression largely absent (Zhang et al, 2018;Quina et al, 2020). Furthermore, early electrophysiological and morphological studies have proposed that a population of neurons akin to the very distinctive cortical neurogliaform interneuron exists within the LHb in rats (Weiss and Veh, 2011;Wagner et al, 2016), although these neurons appear to be different to their cortical counterparts at least in that they do not express similar molecular markers (Webster et al, 2021).…”

Section: Locally-targeting Inhibitory Lhb Neuronsmentioning

confidence: 96%

Inhibition Within the Lateral Habenula—Implications for Affective Disorders

Webster

Lecca

Wozny

2021

Front. Behav. Neurosci.

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The lateral habenula (LHb) is a key brain region implicated in the pathology of major depressive disorder (MDD). Specifically, excitatory LHb neurons are known to be hyperactive in MDD, thus resulting in a greater excitatory output mainly to downstream inhibitory neurons in the rostromedial tegmental nucleus. This likely results in suppression of downstream dopaminergic ventral tegmental area neurons, therefore, resulting in an overall reduction in reward signalling. In line with this, increasing evidence implicates aberrant inhibitory signalling onto LHb neurons as a co-causative factor in MDD, likely as a result of disinhibition of excitatory neurons. Consistently, growing evidence now suggests that normalising inhibitory signalling within the LHb may be a potential therapeutic strategy for MDD. Despite these recent advances, however, the exact pharmacological and neural circuit mechanisms which control inhibitory signalling within the LHb are still incompletely understood. Thus, in this review article, we aim to provide an up-to-date summary of the current state of knowledge of the mechanisms by which inhibitory signalling is processed within the LHb, with a view of exploring how this may be targeted as a future therapy for MDD.

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“…There are strong local glutamatergic connections within the LHb 16,33 , but there is recent evidence both for 34,35 and against 36,37 Fig. 5).…”

Section: Mor Synaptic Function Persists In Lhb Neurons In Animals Witmentioning

confidence: 99%

A diencephalic circuit for opioid analgesia but not positive reinforcement

Waung

Maanum

Driscoll

et al. 2021

Preprint

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Mu opioid receptor (MOR) agonists are the most effective analgesics, but their use risks respiratory depression and addiction. The epithalamic lateral habenula (LHb) is a critical site that signals aversive states, often via indirect inhibition of reward circuitry, and MORs are highly expressed in the LHb. We found that the LHb is a potent site for both MOR-agonist analgesia. Strikingly, LHb MOR activation generates negative reinforcement but is not rewarding in the absence of noxious input. While the LHb receives inputs from multiple sites, we found that inputs from the lateral preoptic area of the hypothalamus (LPO) are excited by noxious stimulation, express MOR mRNA, and are preferentially targeted by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state relieved by LHb MOR activation. Therefore targeting this MOR sensitive forebrain circuit can relieve pain yet lower the risk of misuse by pain free individuals.

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GAD2 Expression Defines a Class of Excitatory Lateral Habenula Neurons in Mice that Project to the Raphe and Pontine Tegmentum

Cited by 30 publications

References 54 publications

GAD65Cre drives reporter expression in multiple taste cell types

GAD65Cre drives reporter expression in multiple taste cell types

Inhibition Within the Lateral Habenula—Implications for Affective Disorders

A diencephalic circuit for opioid analgesia but not positive reinforcement

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