Activation of D1/D5 receptors ameliorates decreased intrinsic excitability of hippocampal neurons induced by neonatal blockade of <i>N</i>‐methyl‐<scp>d</scp>‐aspartate receptors

Griego, Ernesto; Hernández-Frausto, Melissa; Márquez, Luis A; Lara-Valderrábano, Leonardo; López‐Rubalcava, Carolina; Galván, Emilio J.

doi:10.1111/bph.15735

Cited by 10 publications

(25 citation statements)

References 62 publications

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“…Likewise, in patients with trigeminal neuralgia a Ca V 3.2 mutation that increases G max has been recently associated with an increase in the firing frequency of trigeminal ganglion neurons (Gambeta et al, 2022). On the other hand, the acute application of the selective D 1 /D 5 agonist, SKF‐38393, on CA1 pyramidal neurons partially restored electrophysiological alterations on potassium conductances and, consequently, on excitability and firing properties in a model of schizophrenia (Griego et al, 2022). Overall, our results showing a basal Ca V 3 current impairment by D 1 /D 5 receptor constitutive activity support a chronic mechanism that could fine tune neuronal excitability.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activity of the dopamine (D₅) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca_V3.2 and Ca_V3.3 currents

Mustafá

McCarthy

Portales

et al. 2023

British J Pharmacology

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Background and Purpose CaV3.1‐3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein‐coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1‐3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch‐clamp technique. We completed our study with computational modelling and imaging technique. Key Results We found a higher sensitivity to TTA‐P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine‐treated animals compared with vehicle‐treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine‐treated animals in comparison with vehicle‐treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications Native hippocampal CaV3 and recombinant CaV3.2‐3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy.

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Section: Discussionmentioning

confidence: 99%

Constitutive activity of the dopamine (D₅) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca_V3.2 and Ca_V3.3 currents

Mustafá

McCarthy

Portales

et al. 2023

British J Pharmacology

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“…With these configurations, we observed comparable performance between groups, allowing us to evaluate spatial memory retrieval confidently. (Griego, Hernández-Frausto, et al, 2022). Additional analysis of passive electrophysiological membrane properties, including RMP, R N , τ mem , and I Rheo revealed no changes of MK-treated CA3 PCs compared with control cells (Table 1).…”

Section: Barnes Maze Taskmentioning

confidence: 90%

“…Further to this observation, multiple experimental approaches based on genetic deletion or pharmacological blockade of NMDARs have uncovered a series of disturbances at the molecular, synaptic, and behavioral level that mimics negative and cognitive symptoms of schizophrenia (Kjaerby et al, 2017; Segev et al, 2020; Seshadri et al, 2018; Wang et al, 2001). For instance, neonatal blockade of NMDARs with the non‐competitive antagonist MK‐801 dysregulates the γ‐aminobutyric acid (GABA)‐ergic transmission of the hippocampus (Ikonomidou et al, 1999; Li et al, 2015) and alters induction and expression of the NMDAR‐dependent, long‐term potentiation of hippocampal area CA1 (Griego, Hernández‐Frausto, et al, 2022; Liu et al, 2009; Yang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, neonatal blockade of NMDARs with the non-competitive antagonist MK-801 dysregulates the γ-aminobutyric acid (GABA)-ergic transmission of the hippocampus (Ikonomidou et al, 1999;Li et al, 2015) and alters induction and expression of the NMDAR-dependent, long-term potentiation of hippocampal area CA1 (Griego, Hernández-Frausto, et al, 2022;Liu et al, 2009;Yang et al, 2014).…”

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confidence: 99%

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NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells

et al. 2023

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Experimental manipulations that interfere with the functional expression of N‐methyl‐D‐aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK‐801 during early postnatal development alters glutamate release and impairs the induction of NMDAR‐dependent long‐term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR)‐mediated short‐ and long‐term potentiation, are compromised in response to neonatal treatment with MK‐801. Consistent with this tenet, short‐ and long‐term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole‐cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre‐ and postsynaptic modifications at the MF—CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired‐pulse ratio, and reduced AMPAR‐mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK‐801‐treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR‐independent forms of synaptic plasticity of the hippocampus.

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“…By injecting 1 mg/kg of intraperitoneal lipopolysaccharide (LPS), the activation of the immune system is triggered and 24 h later they have studied the changes that occur in the properties of these cells [ 150 ]. The modulation of ion channels underlying passive and active membrane conductances is a critical element for expressing potentiation of intrinsic excitability [ 151 , 152 ]. In this study, neurons treated with LPS show increased activity of Na + (INa) currents as the functionality of Na + channels increases.…”

Section: Impact Of Oxidative Stress In Motor Cortex Neurons Hyperexci...mentioning

confidence: 99%

Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases

et al. 2022

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Neurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems that produce brain damage from which there is no recovery. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear to be similar, suggesting common neurodegenerative pathways. It is well known that oxidative stress and the production of reactive oxygen radicals plays a key role in neuronal cell damage. It has been proposed that this stress, among other mechanisms, could contribute to neuronal degeneration and might be one of the factors triggering the development of these pathologies. Another common feature in most neurodegenerative diseases is neuron hyperexcitability, an aberrant electrical activity. This review, focusing mainly on primary motor cortex pyramidal neurons, critically evaluates the idea that oxidative stress and inflammation may be involved in neurodegeneration via their capacity to increase membrane excitability.

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Activation of D1/D5 receptors ameliorates decreased intrinsic excitability of hippocampal neurons induced by neonatal blockade of N‐methyl‐d‐aspartate receptors

Abstract: Background and Purpose: Dysregulation of dopaminergic transmission combined with transient hypofunction of N-methyl-D-aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia.

Cited by 10 publications

References 62 publications

Constitutive activity of the dopamine (D₅) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca_V3.2 and Ca_V3.3 currents

Constitutive activity of the dopamine (D₅) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca_V3.2 and Ca_V3.3 currents

NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells

Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases

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Activation of D1/D5 receptors ameliorates decreased intrinsic excitability of hippocampal neurons induced by neonatal blockade of N‐methyl‐d‐aspartate receptors

Abstract: Background and Purpose: Dysregulation of dopaminergic transmission combined with transient hypofunction of N-methyl-D-aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia.

Cited by 10 publications

References 62 publications

Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents

Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents

NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells

Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases

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Constitutive activity of the dopamine (D₅) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca_V3.2 and Ca_V3.3 currents

Constitutive activity of the dopamine (D₅) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca_V3.2 and Ca_V3.3 currents