scholarly journals GABAB receptor/HCN channel complexes in VTA dopamine neurons limit synaptic inhibition and prevent anxiety-like behavior

2021 ◽  
Author(s):  
Bernhard Bettler ◽  
Giogio Rizzi ◽  
Thorsten Fritzius ◽  
Enrique Perez-Garci ◽  
Alessandra Porcu ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Gabab Receptor ◽  
Dopamine Neurons ◽  
Hcn Channels ◽  
Synaptic Inhibition ◽  
Hcn Channel ◽  
Wild Type ◽  
Aversive Stimuli ◽  
Physiological Relevance

Aversive stimuli inhibiting dopamine neurons in the ventral tegmental area (DAVTA neurons) induce anxiety-like behaviors. The inhibition of DAVTA neurons is prolonged by GABAB receptor (GBR)-activated K+-currents, which exhibit a rapid desensitization of unknown physiological relevance. We now report that GBRs associate via auxiliary KCTD16 subunits with HCN channels, which facilitates activation of hyperpolarization activated currents (Ih) by GBR-activated K+ currents. Activation of Ih underlies rapid K+ current desensitization in DAVTA neurons and limits GBR-mediated inhibition. Disruption of the GBR/HCN complex in KCTD16-/- mice or blockade of Ih prolongs optogenetically driven inhibition of DAVTA neuron firing. KCTD16-/- mice exhibit an increased anxiety-like behavior in response to stressful stimuli, which is reproduced by in vivo CRISPR/Cas9-mediated KCTD16 ablation in DAVTA neurons or intra-VTA infusion of HCN antagonist to wild-type mice. Our data reveal that GBR-induced Ih protect DAVTA neurons from prolonged GBR mediated inhibition in response to stressors, which moderates anxiety-like behaviors.

scholarly journals Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

2021 ◽  
pp. 1-24
Author(s):  
Juho-Matti Renko ◽  
Arun Kumar Mahato ◽  
Tanel Visnapuu ◽  
Konsta Valkonen ◽  
Mati Karelson ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Disease Modifying Therapy ◽  
Immortalized Cells ◽  
Midbrain Dopamine ◽  
6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

scholarly journals Rescue of defective G protein–coupled receptor function in vivo by intermolecular cooperation

2010 ◽  
Vol 107 (5) ◽  
pp. 2319-2324 ◽  
Author(s):  
Adolfo Rivero-Müller ◽  
Yen-Yin Chou ◽  
Inhae Ji ◽  
Svetlana Lajic ◽  
Aylin C. Hanyaloglu ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Luteinizing Hormone Receptor ◽  
Wild Type ◽  
Gpcr Signaling ◽  
Physiological Relevance ◽  
Biosynthesis Activation ◽  
Mutant Receptors ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.

scholarly journals Epoxide hydrolase 3 (Ephx3) gene disruption reduces ceramide linoleate epoxide hydrolysis and impairs skin barrier function

2020 ◽  
pp. jbc.RA120.016570
Author(s):  
Matthew L. Edin ◽  
Haruto Yamanashi ◽  
William E. Boeglin ◽  
Joan P. Graves ◽  
Laura M. DeGraff ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Skin Barrier ◽  
Skin Barrier Function ◽  
Potential Contribution ◽  
Wild Type ◽  
Lipoxygenase Pathway ◽  
Physiological Relevance ◽  
Hydrolysis Of

The mammalian epoxide hydrolase EPHX3 is known from in vitro experiments to efficiently hydrolyze the linoleate epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo.  Ephx3-/- mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12R-lipoxygenase pathway are reduced. Although the Ephx3-/- pups appear normal, measurements of trans-epidermal water loss detected a modest and statistically significant increase compared to the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal epoxide hydrolase (EPHX1/mEH) or soluble epoxide hydrolase (EPHX2/sEH). This barrier phenotype in the Ephx3-/- pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p<0.05), indicating a corresponding structural impairment in the integrity of the water barrier. Quantitative LC-MS analysis of the esterified linoleate-derived triols in the murine epidermis revealed a marked and isomer-specific reduction (~85%) in the Ephx3-/- epidermis of the major trihydroxy isomer 9R,10S,13R-trihydroxy-11E-octadecenoate. We conclude EPHX3 (and not EPHX1 or EPHX2) catalyzes hydrolysis of the 12R-LOX/eLOX3-derived epoxyalcohol esterified in acylceramide, and may function to control flux through the alternative and crucial route of metabolism via the dehydrogenation pathway of SDR9C7. Importantly, our findings also identify a functional role for EPHX3 in transformation of a naturally esterified epoxide substrate, pointing to its potential contribution in other tissues.

scholarly journals Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat

2016 ◽  
Vol 116 (3) ◽  
pp. 1161-1174 ◽  
Author(s):  
P. Leon Brown ◽  
Paul D. Shepard
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Lateral Habenula ◽  
Aversive Stimuli ◽  
Rat Pups ◽  
Tegmental Nucleus ◽  
Fasciculus Retroflexus ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience.

scholarly journals HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Peng Zhong ◽  
Casey R Vickstrom ◽  
Xiaojie Liu ◽  
Ying Hu ◽  
Laikang Yu ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Chronic Stress ◽  
Ex Vivo ◽  
Critical Role ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Hcn Channels ◽  
Neuron Firing ◽  
Ventral Tegmental

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

Slow Oscillatory Firing: A Major Firing Pattern of Dopamine Neurons in the Ventral Tegmental Area

2005 ◽  
Vol 94 (5) ◽  
pp. 3516-3522 ◽  
Author(s):  
Wei-Xing Shi
Keyword(s):  
Ventral Tegmental Area ◽  
Single Unit ◽  
Firing Pattern ◽  
Receptor Activation ◽  
Dopamine Neurons ◽  
Interspike Intervals ◽  
Firing Activity ◽  
Unit Recording ◽  
Ventral Tegmental

Using spectral analysis and in vivo single-unit recording in rats, the present study revealed a pronounced slow oscillation (SO) in the firing activity of about half the dopamine (DA) neurons recorded in the ventral tegmental area. DA neurons in this group tended to fire repetitive spike clusters, making them appear to be rhythmic bursting cells. However, only some of these burst-like events met the traditional “80/160 ms” burst criteria entirely. The observation that the SO could be found in nonbursting DA cells, occurred at frequencies different from those of bursts, and persisted after bursts were digitally removed from spike trains further supports the suggestion that the SO is different from the traditionally defined bursting. Interspike intervals (ISIs) had been thought to be bimodally distributed in bursting DA neurons. This study found that some nonbursting DA cells also had a bimodal ISI distribution and a significant number of bursting cells did not. In the majority of cells where less than half the spikes occurred in bursts, a bimodal ISI distribution was highly predictive of the presence of the SO. Results further showed that the generation of the SO required forebrain inputs to DA neurons but not the adrenergic α1 receptor activation responsible for psychostimulant-induced increases in the SO. Taken together, these results suggest that the SO is distinct from the traditionally defined bursting and represents a major firing pattern of DA neurons in the ventral tegmental area.

Long-lasting synaptic regulation of dopamine neurons by astrocytes in the Ventral Tegmental Area

2021 ◽  
Author(s):  
Linda Requie ◽  
Marta Gómez-Gonzalo ◽  
Francesca Managò ◽  
Mauro Congiu ◽  
Marcello Melone ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Astrocytic Process ◽  
Metabotropic Glutamate ◽  
Ventral Tegmental

Abstract The plasticity of glutamatergic transmission in the Ventral Tegmental Area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and the phasic dopamine release at VTA target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated-behaviors. Here we describe a hitherto unidentified mechanism of long-lasting potentiation of glutamatergic synapses on DA neurons. We found that VTA astrocytes respond to dopamine neuron bursts with Ca2+ elevations that require activation of endocannabinoid CB1 and dopamine D2 receptors colocalized at the same astrocytic process. Astrocytes, in turn, release glutamate that, through presynaptic metabotropic glutamate receptor activation coupled with neuronal nitric oxide production, induces long-lasting potentiation of excitatory synapses on adjacent dopamine neurons. Consistent with this finding, selective activation of VTA astrocytes increases dopamine neuron bursts in vivo and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron activity.

scholarly journals Interneuron Transplantation Creates New Network States and Rescues Social Behavior Deficits in a Mouse Model of Autism

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Derek Southwell ◽  
Helia Seifikar ◽  
Ruchi Malik ◽  
Karen Lavi ◽  
Daniel Vogt ◽  
...  
Keyword(s):  
Social Behavior ◽  
Neuropsychiatric Disorders ◽  
Inhibitory Interneuron ◽  
Network Activity ◽  
Therapeutic Effects ◽  
Synaptic Inhibition ◽  
Behavioral State ◽  
Wild Type

Abstract INTRODUCTION Inhibitory interneuron transplantation is a prospective treatment for neuropsychiatric disorders, but it is unclear whether transplantation might elicit therapeutic effects by reversing preexisting abnormalities, nonspecifically increasing synaptic inhibition, or engaging mechanisms that vary depending on recipient background and behavioral state. METHODS We transplanted wild-type embryonic interneuron precursors into mice lacking an autism-associated gene, Pten, in inhibitory interneurons. Additionally, we performed transplantation into wild-type recipient mice, and then examined the recipient behavior, cellular physiology in Vitro, and network physiology in Vivo. RESULTS Transplantation rescued social behavior deficits in Pten mutants without normalizing excessive synaptic inhibition in Vitro or reduced baseline gamma oscillatory power in Vivo. However, transplantation altered recipient electroencephalography (EEG) responses observed specifically during periods of social interaction. When transplantation was performed into wild-type recipients, the subtype composition of the transplanted population varied from that observed in Pten mutants, and, moreover, recipients did not exhibit alterations to social behavior or related EEG responses. CONCLUSION Interneuron transplantation elicits recipient- and behavioral state-dependent effects, and normalizes behavior by creating new patterns of network activity, rather than restoring wild-type states. Interneuron transplantation may provide a novel therapeutic approach to the treatment of autism and related neuropsychiatric disorders.

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