RESUMEN
Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.
Asunto(s)
Enfermedades Neurodegenerativas , Receptores de Glutamato Metabotrópico , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Transducción de Señal/fisiología , Ácido Glutámico , Neurotransmisores , Neuronas , Receptores de Glutamato Metabotrópico/fisiologíaRESUMEN
Glutamate, the major excitatory neurotransmitter in the brain exerts its effects via both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). There are three subgroups of mGluRs, pre-synaptic Group II and Group III mGluRs and post-synaptic Group I mGluRs. mGluRs are ubiquitously expressed in the brain and their activation is poised upstream of a myriad of signaling pathways, resulting in their implication in the pathogenesis of various neurodegenerative diseases including, Alzheimer's Disease (AD). While the exact mechanism of AD etiology remains elusive, ß-amyloid (Aß) plaques and hyperphosphorylated tau tangles remain the histopathological hallmarks of AD. Though less electrically excitable, neuroglia are a major non-neuronal cell type in the brain and are composed of astrocytes, microglia, and oligodendrocytes. Astrocytes, microglia, and oligodendrocytes provide structural and metabolic support, active immune defence, and axonal support and sheathing, respectively. Interestingly, Aß and hyperphosphorylated tau are known to disrupt the neuroglial homeostasis in the brain, pushing them towards a more neurotoxic state. In this review, we discuss what is currently known regarding the expression patterns of various mGluRs in neuroglia and how Aß and tau alter the normal mGluR function in the neuroglia and contribute to the pathophysiology of AD.
Asunto(s)
Enfermedad de Alzheimer , Receptores de Glutamato Metabotrópico , Humanos , Enfermedad de Alzheimer/metabolismo , Receptores de Glutamato Metabotrópico/fisiología , Neuroglía/metabolismo , Péptidos beta-Amiloides/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Alzheimer's disease (AD) was first identified more than 100 years ago, yet aspects pertaining to its origin and the mechanisms underlying disease progression are not well known. To this date, there is no therapeutic approach or disease-modifying drug that could halt or at least delay disease progression. Until recently, glial cells were seen as secondary actors in brain homeostasis. Although this view was gradually refuted and the relevance of glial cells for the most diverse brain functions such as synaptic plasticity and neurotransmission was vastly proved, many aspects of its functioning, as well as its role in pathological conditions, remain poorly understood. Metabotropic glutamate receptors (mGluRs) in glial cells were shown to be involved in neuroinflammation and neurotoxicity. Besides its relevance for glial function, glutamatergic receptors are also central in the pathology of AD, and recent studies have shown that glial mGluRs play a role in the establishment and progression of AD. AD-related alterations in Ca2+ signalling, APP processing, and Aß load, as well as AD-related neurodegeneration, are influenced by glial mGluRs. However, different types of mGluRs play different roles, depending on the cell type and brain region that is being analysed. Therefore, in this review, we focus on the current understanding of glial mGluRs and their implication in AD, providing an insight for future therapeutics and identifying existing research gaps worth investigating.
Asunto(s)
Enfermedad de Alzheimer , Receptores de Glutamato Metabotrópico , Humanos , Enfermedad de Alzheimer/patología , Receptores de Glutamato Metabotrópico/fisiología , Neuroglía/metabolismo , Transducción de Señal/fisiología , Progresión de la EnfermedadRESUMEN
Metabotropic glutamate receptors (mGluRs) have been discovered almost four decades ago. Since then, their pharmacology has been largely developed as well as their structural organization. Indeed mGluRs are attractive therapeutic targets for numerous psychiatric and neurological disorders because of their modulating role of synaptic transmission. The more recent drug discovery programs have mostly concentrated on allosteric modulators. However, orthosteric agonists and antagonists have remained unavoidable pharmacological tools as, although not expected, many of them can reach the brain, or can be modified to reach the brain. This review focuses on the most common orthosteric ligands as well as on the few allosteric modulators interacting with the glutamate binding domain. The 3D-structures of these ligands at their binding sites are reported. For most of them, X-Ray structures or docked homology models are available. Because of the high conservation of the binding site, subtype selective agonists were not easy to find. Yet, some were discovered when extending their chemical structures in order to reach selective sites of the receptors.
Asunto(s)
Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica , Sitios de Unión , Descubrimiento de Drogas , Humanos , Ligandos , Conformación Molecular , Terapia Molecular Dirigida , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/fisiología , Transmisión SinápticaRESUMEN
On the occasion of the 40 year anniversary of the hugely impactful review by Richard (Dick) Evans and Jeff Watkins, we describe how their work has impacted the field of synaptic plasticity. We describe their influence in each of the major glutamate receptor subtypes: AMPARs, NMDARs, KARs and mGluRs. Particular emphasis is placed on how their work impacted our own studies in the hippocampus. For example, we describe how the tools and regulators that they identified for studying NMDARs (e.g., NMDA, D-AP5 and Mg2+) led to the understanding of the molecular basis of the induction of LTP. We also describe how other tools that they introduced (e.g., (1S,3R)-ACPD and MCPG) helped lead to the concept of metaplasticity.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/metabolismo , Magnesio/farmacología , Plasticidad Neuronal/fisiología , Neurofarmacología/historia , Receptores Ionotrópicos de Glutamato/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Animales , Hipocampo/efectos de los fármacos , Historia del Siglo XX , Humanos , Plasticidad Neuronal/efectos de los fármacos , Receptores Ionotrópicos de Glutamato/efectos de los fármacos , Receptores de Glutamato Metabotrópico/efectos de los fármacosRESUMEN
Degenerative diseases of the retina are responsible for the death of photoreceptors and subsequent loss of vision in patients. Nevertheless, the inner retinal layers remain intact over an extended period of time, enabling the restoration of light sensitivity in blind retinas via the expression of optogenetic tools in the remaining retinal cells. The chimeric Opto-mGluR6 protein represents such a tool. With exclusive ON-bipolar cell expression, it combines the light-sensitive domains of melanopsin and the intracellular domains of the metabotropic glutamate receptor 6 (mGluR6), which naturally mediates light responses in these cells. Albeit vision restoration in blind mice by Opto-mGluR6 delivery was previously shown, much is left to be explored in regard to the effects of the timing of the treatment in the degenerated retina. We performed a functional evaluation of Opto-mGluR6-treated murine blind retinas using multi-electrode arrays (MEAs) and observed long-term functional preservation in the treated retinas, as well as successful therapeutical intervention in later stages of degeneration. Moreover, the treatment decreased the inherent retinal hyperactivity of the degenerated retinas to levels undistinguishable from healthy controls. Finally, we observed for the first time micro electroretinograms (mERGs) in optogenetically treated animals, corroborating the origin of Opto-mGluR6 signalling at the level of mGluR6 of ON-bipolar cells.
Asunto(s)
Terapia Genética/métodos , Optogenética/métodos , Células Bipolares de la Retina/fisiología , Degeneración Retiniana/terapia , Animales , Ceguera/genética , Ceguera/fisiopatología , Ceguera/terapia , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Modelos Animales de Enfermedad , Electrorretinografía , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/fisiología , Degeneración Retiniana/genética , Degeneración Retiniana/fisiopatología , Transducción de Señal , Visión Ocular/fisiologíaRESUMEN
Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) is one of the diffusible messengers for enhancing synaptic transmission in the hippocampus. Less information is available about the possible roles of BDNF in the anterior cingulate cortex (ACC). In the present study, we used 64-electrode array field recording system to investigate the effect of BDNF on ACC excitatory transmission. We found that BDNF enhanced synaptic responses in a dose-dependent manner in the ACC in C57/BL6 mice. The enhancement was long-lasting, and persisted for at least 3 h. In addition to the enhancement, BDNF also recruited inactive synaptic responses in the ACC. Bath application of the tropomyosin receptor kinase B (TrkB) receptor antagonist K252a blocked BDNF-induced enhancement. L-type voltage-gated calcium channels (L-VGCC), metabotropic glutamate receptors (mGluRs), but not NMDA receptors were required for BDNF-produced enhancement. Moreover, calcium-stimulated adenylyl cyclase subtype 1 (AC1) but not AC8 was essential for the enhancement. A selective AC1 inhibitor NB001 completely blocked the enhancement. Furthermore, BDNF-produced enhancement occluded theta burst stimulation (TBS) induced long-term potentiation (LTP), suggesting that they may share similar signaling mechanisms. Finally, the expression of BDNF-induced enhancement depends on postsynaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) and protein kinase Mζ (PKMζ). Our results demonstrate that cortical BDNF may contribute to synaptic potentiation in the ACC.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Giro del Cíngulo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Sinapsis/efectos de los fármacos , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Adenilil Ciclasas/fisiología , Animales , Canales de Calcio Tipo L/fisiología , Carbazoles/farmacología , Relación Dosis-Respuesta a Droga , Electrodos Implantados , Alcaloides Indólicos/farmacología , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa C/fisiología , Receptores AMPA/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Sinapsis/fisiología , Ritmo Teta/efectos de los fármacosRESUMEN
Somatostatin-expressing interneurons (SOM-INs) are a major subpopulation of GABAergic cells in CA1 hippocampus that receive excitation from pyramidal cells (PCs), and, in turn, provide feedback inhibition onto PC dendrites. Excitatory synapses onto SOM-INs show a Hebbian long-term potentiation (LTP) mediated by type 1a metabotropic glutamate receptors (mGluR1a) that is implicated in hippocampus-dependent learning. The neuropeptide somatostatin (SST) is also critical for hippocampal long-term synaptic plasticity, as well as learning and memory. SST effects on hippocampal PCs are well documented, but its actions on inhibitory interneurons remain largely undetermined. In the present work, we investigate the involvement of SST in long-term potentiation of CA1 SOM-IN excitatory synapses using pharmacological approaches targeting the somatostatinergic system and whole cell recordings in slices from transgenic mice expressing eYFP in SOM-INs. We report that application of exogenous SST14 induces long-term potentiation of excitatory postsynaptic potentials in SOM-INs via somatostatin type 1-5 receptors (SST1-5Rs) but does not affect synapses of PC or parvalbumin-expressing interneurons. Hebbian LTP in SOM-INs was prevented by inhibition of SSTRs and by depletion of SST by cysteamine treatment, suggesting a critical role of endogenous SST in LTP. LTP of SOM-IN excitatory synapses induced by SST14 was independent of NMDAR and mGluR1a, activity-dependent, and prevented by blocking GABAA receptor function. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses of SOM-INs by controlling GABAA inhibition, uncovering a novel role for SST in regulating long-term synaptic plasticity in somatostatinergic cells that may be important for hippocampus-dependent memory processes.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Interneuronas/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Somatostatina/fisiología , Sinapsis/efectos de los fármacos , Animales , Proteínas Bacterianas , Cisteamina/farmacología , Femenino , Antagonistas de Receptores de GABA-A/farmacología , Neuronas GABAérgicas/metabolismo , Técnicas de Sustitución del Gen , Genes Reporteros , Humanos , Interneuronas/metabolismo , Proteínas Luminiscentes , Masculino , Memoria/fisiología , Ratones , Ratones Transgénicos , Péptidos Cíclicos/farmacología , Receptores de Glutamato Metabotrópico/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Receptores de Somatostatina/efectos de los fármacos , Receptores de Somatostatina/fisiología , Somatostatina/farmacología , Sinapsis/fisiologíaRESUMEN
Astroglial cells were long considered as structural and metabolic supporting cells are which do not directly participate in information processing in the brain. Discoveries of responsiveness of astrocytes to synaptically-released glutamate and their capability to release agonists of glutamate receptors awakened extensive studies of glia-neuron communications and led to the revolutionary changes in our understanding of brain cellular networks. Nowadays, astrocytes are widely acknowledged as inseparable element of glutamatergic synapses and role for glutamatergic astrocyte-neuron interactions in the brain computation is emerging. Astroglial glutamate receptors, in particular of NMDA, mGluR3 and mGluR5 types, can activate a variety of molecular cascades leading astroglial-driven modulation of extracellular levels of glutamate and activity of neuronal glutamate receptors. Their preferential location to the astroglial perisynaptic processes facilitates interaction of astrocytes with individual excitatory synapses. Bi-directional glutamatergic communication between astrocytes and neurons underpins a complex, spatially-distributed modulation of synaptic signalling thus contributing to the enrichment of information processing by the neuronal networks. Still, further research is needed to bridge the substantial gaps in our understanding of mechanisms and physiological relevance of astrocyte-neuron glutamatergic interactions, in particular ability of astrocytes directly activate neuronal glutamate receptors by releasing glutamate and, arguably, d-Serine. An emerging roles for aberrant changes in glutamatergic astroglial signalling, both neuroprotective and pathogenic, in neurological and neurodegenerative diseases also require further investigation. This article is part of the special Issue on 'Glutamate Receptors - The Glutamatergic Synapse'.
Asunto(s)
Astrocitos/fisiología , Neuroglía/fisiología , Plasticidad Neuronal/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , HumanosRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles. Aß oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP61). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aß toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aß-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP61, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca2+-permeable GluA2-lacking AMPA receptors along with higher STEP61 levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-ß has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.
Asunto(s)
Depresión Sináptica a Largo Plazo/fisiología , Neuronas/fisiología , Proteínas Tirosina Fosfatasas no Receptoras/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Proteína Reelina/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Calcio/fisiología , Células Cultivadas , Corteza Cerebral/citología , Inducción Enzimática/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Memoria/fisiología , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Ratones , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Picrotoxina/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Proteínas Recombinantes/metabolismo , Proteína Reelina/deficiencia , Proteína Reelina/genéticaRESUMEN
Hypoxic ischemic brain injury (HIBI) has been one of the most severe central nervous system (CNS) diseases with high fatality and disability rate. Neural stem cells (NSCs) persist in the mammalian brain throughout life and NSCs-associated therapies might be a promising strategy for the HIBI treatment. In this study, we identified that type 4 metabotropic glutamate receptor (mGluR4) was expressed in cultured human NSCs (hNSCs) isolated from the human fetus cortex and further established the oxygen and glucose deprivation (OGD) model in hNSCs to study the role of mGluR4 in hypoxic and ischemic injury. The results indicated that mGluR4 activation by using VU0155041 (mGluR4-specific agonist) markedly attenuated the OGD-induced alterations in TUNEL staining, apoptosis rate, cleavages of pro-caspase-8, -9, -3, and Bcl-2/Bax expression balance. Furthermore, mGluR4 activation inhibited the ASK1/p38 signaling pathway. Asiatic acid, as a p38 MAPK activator, is capable of abolishing the neuroprotective effect of mGluR4, while both NQDI-1 (ASK-1 inhibitor) and SB203580 (p38 MAPK inhibitor) exerted similar effects to VU0155041 in the OGD-induced hNSC damage. In conclusion, this study indicates that mGluR4 activation protects hNSCs against the OGD-induced cell death via inhibiting the ASK1-p38 pathway. Activation of mGluR4 might be a promising strategy for enhancing NSCs survival in hypoxic and ischemic injury.
Asunto(s)
Hipoxia-Isquemia Encefálica/terapia , MAP Quinasa Quinasa Quinasa 5/metabolismo , Células-Madre Neurales/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glucosa/deficiencia , Glucosa/metabolismo , Humanos , Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores , Oxígeno/metabolismo , Receptores de Glutamato Metabotrópico/fisiología , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Enigmatic orphan glutamate delta receptors (GluD) are one of the four classes of the ionotropic glutamate receptors (iGluRs) that play key roles in synaptic transmission and plasticity. While members of other iGluR families viz AMPA, NMDA, and kainate receptors are gated by glutamate, the GluD receptors neither bind glutamate nor evoke ligand-induced currents upon binding of glycine and D-serine. Thus, the GluD receptors were considered to function as structural proteins that facilitate the formation, maturation, and maintenance of synapses in the hippocampus and cerebellum. Recent work has revealed that GluD receptors have extensive crosstalk with metabotropic glutamate receptors (mGlus) and are also gated by their activation. The latest development of a novel optopharamcological tool and the cryoEM structures of GluD receptors would help define the molecular and chemical basis of the GluD receptor's role in synaptic physiology. This article is part of the special Issue on "Glutamate Receptors - Orphan iGluRs".
Asunto(s)
Receptores de Glutamato/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Cerebelo , Microscopía por Crioelectrón , Hipocampo , Humanos , Plasticidad Neuronal/fisiología , Receptores de Glutamato/fisiología , Receptores de Glutamato/ultraestructura , Receptores Ionotrópicos de Glutamato/metabolismo , Receptores Ionotrópicos de Glutamato/fisiología , Receptores Ionotrópicos de Glutamato/ultraestructura , Receptores de Glutamato Metabotrópico/fisiología , Relación Estructura-ActividadRESUMEN
Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/fisiología , Giro del Cíngulo/citología , Giro del Cíngulo/fisiología , Células Piramidales/fisiología , Animales , Clozapina/análogos & derivados , Clozapina/farmacología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/efectos de los fármacos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Expresión Génica/efectos de los fármacos , Giro del Cíngulo/efectos de los fármacos , Humanos , Conducta Impulsiva/efectos de los fármacos , Conducta Impulsiva/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Piramidales/citología , Células Piramidales/efectos de los fármacos , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/fisiología , Transducción de SeñalRESUMEN
Purpose: The three-dimensional configurations of rod and cone bipolar cell (BC) dendrites and horizontal cell (HC) processes outside rod and cone synaptic terminals have not been fully elucidated. We reveal how these neurites are mutually arranged to coordinate formation and maintenance of the postsynaptic complex of ribbon synapses in mouse and monkey retinas. Methods: Serial section transmission electron microscopy was utilized to reconstruct BC and HC neurites in macaque monkey and mouse, including metabotropic glutamate receptor 6 (mGluR6)-knockout mice. Results: Starting from sporadically distributed branching points, rod BC and HC neurites (B and H, respectively) took specific paths to rod spherules by gradually adjusting their mutual positions, which resulted in a closed alternating pattern of HâBâHâB neurites at the rod spherule aperture. This order corresponded to the array of elements constituting the postsynaptic complex of ribbon synapses. We identified novel helical coils of HC processes surrounding the rod BC dendrite in both mouse and macaque retinas, and these structures occurred more frequently in mGluR6-knockout than wild-type mouse retinas. Horizontal cell processes also formed hook-like protrusions that encircled cone BC and HC neurites below the cone pedicles in the macaque retina. Conclusions: Bipolar and horizontal cell neurites take specific paths to adjust their mutual positions at the rod spherule aperture. Some HC processes are helically coiled around rod BC dendrites or form hook-like protrusions around cone BC dendrites and HC processes. Loss of mGluR6 signaling may be one factor promoting unbalanced neurite growth and compensatory neurite coiling.
Asunto(s)
Fasciculación Axonal/fisiología , Neuritas/ultraestructura , Células Bipolares de la Retina/ultraestructura , Células Horizontales de la Retina/ultraestructura , Células Fotorreceptoras Retinianas Bastones/ultraestructura , Vías Visuales/ultraestructura , Animales , Femenino , Macaca fuscata , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Terminales Presinápticos , Receptores de Glutamato Metabotrópico/fisiología , SinapsisRESUMEN
BACKGROUND: The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus). METHODS: In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1 day after 4 to 5 weeks of intermittent access (IA) EtOH exposure. RESULTS: Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu2/3 receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking. CONCLUSIONS: Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu2 and/or mGlu3 receptor function as potential treatments for AUD.
Asunto(s)
Etanol/administración & dosificación , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Sinapsis/fisiología , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Sinapsis/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-ß (Aß), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Plasticidad Neuronal , Receptores de Glutamato Metabotrópico/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/fisiopatología , Humanos , Receptores de Glutamato Metabotrópico/fisiologíaRESUMEN
The ability of humans and animals to localize the source of a sound in a complex acoustic environment facilitates communication and survival. Two cues are used for sound localization at horizontal planes, interaural time and level differences (ITD and ILD), which are analyzed by distinct neural circuits in the brainstem. Here, we review the studies on metabotropic glutamate receptor (mGluR)-mediated neuromodulation of both intrinsic and synaptic properties of brainstem neurons in these circuits. Both mammalian and avian animal models have been used, with each having their advantages that are not present in the other. For the mammalian model, we discuss mGluR neuromodulation in the ILD circuit, with an emphasis on the recent discovery of differential modulation of synaptic transmission of different transmitter release modes. For the avian model, we focus on reviewing mGluR neuromodulation in the ITD pathway, with an emphasis on tonotopic distribution and synaptic plasticity of mGluR modulation in coincidence detector neurons. Future works are proposed to further investigate the functions and mechanisms of mGluRs in the sound localization circuits.
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Vías Auditivas/metabolismo , Tronco Encefálico/metabolismo , Núcleo Coclear/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Localización de Sonidos/fisiología , Animales , Vías Auditivas/fisiología , Aves , Tronco Encefálico/fisiología , Núcleo Coclear/fisiología , Humanos , Ratones , Receptores de Glutamato Metabotrópico/fisiologíaRESUMEN
Antagonists of the group II metabotropic glutamate (mGlu) 2/3 receptors have been shown to have a rapid antidepressant effect. GABAergic interneurons play a crucial role in major depressive disorder (MDD) and possibly mediate the rapid antidepressant effect. However, how mGlu2/3 receptors regulate synaptic activities to GABAergic interneurons is not fully understood. In the present work, we studied the effect of mGlu2/3 receptors on excitatory and inhibitory synaptic activities to somatostatin (SST)- and parvalbumin (PV)-expressing interneurons, two major types of GABAergic interneurons, in the anterior cingulate cortex (ACC) that is strongly indicated in MDD. We found that activation of mGlu2/3 receptors by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCG-IV), an agonist of mGlu2/3 receptors, remarkably reduced the frequency, but not the amplitude, of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) and the amplitude of evoked EPSCs in both types. The reduction in the frequency of sEPSCs and the amplitude of evoked EPSCs was more pronounced in SST interneurons. DCG-IV, however, did not affect spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and evoked IPSCs in both types. LY341495, an antagonist of mGlu2/3 receptors, enhanced the amplitude of evoked EPSCs without affecting sEPSCs and mEPSCs in both types. It also did not affect sIPSCs and evoked IPSCs except slightly increasing the frequency of mIPSCs in SST interneurons. Our results indicate that mGlu2/3 receptors primarily regulate excitatory synaptic activities to the two types of GABAergic interneurons in the ACC.
Asunto(s)
Neuronas GABAérgicas/fisiología , Giro del Cíngulo/fisiología , Interneuronas/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Sinapsis/fisiología , Animales , Masculino , Potenciales de la Membrana , Ratones Endogámicos C57BLRESUMEN
Transient receptor potential canonical (TRPC) proteins constitute a group of receptor-operated calcium-permeable nonselective cationic membrane channels of the TRP superfamily. They are largely expressed in the hippocampus and are able to modulate neuronal functions. Accordingly, they have been involved in different hippocampal functions such as learning processes and different types of memories, as well as hippocampal dysfunctions such as seizures. This review covers the mechanisms of activation of these channels, how these channels can modulate neuronal excitability, in particular the after-burst hyperpolarization, and in the persistent activity, how they control synaptic plasticity including pre- and postsynaptic processes and how they can interfere with cell survival and neurogenesis.