RESUMEN

Sensory experiences and learning induce long-lasting changes in both excitatory and inhibitory synapses, thereby providing a crucial substrate for memory. However, the co-tuning of excitatory long-term potentiation (eLTP) or depression (eLTD) with the simultaneous changes at inhibitory synapses (iLTP/iLTD) remains unclear. Herein, we investigated the co-expression of NMDA-induced synaptic plasticity at excitatory and inhibitory synapses in hippocampal CA1 pyramidal cells (PCs) using a combination of electrophysiological, optogenetic, and pharmacological approaches. We found that inhibitory inputs from somatostatin (SST) and parvalbumin (PV)-positive interneurons onto CA1 PCs display input-specific long-term plastic changes following transient NMDA receptor activation. Notably, synapses from SST-positive interneurons consistently exhibited iLTP, irrespective of the direction of excitatory plasticity, whereas synapses from PV-positive interneurons predominantly showed iLTP concurrent with eLTP, rather than eLTD. As neuroplasticity is known to depend on the extracellular matrix, we tested the impact of metalloproteinases (MMP) inhibition. MMP3 blockade interfered with GABAergic plasticity for all inhibitory inputs, whereas MMP9 inhibition selectively blocked eLTP and iLTP in SST-CA1PC synapses co-occurring with eLTP but not eLTD. These findings demonstrate the dissociation of excitatory and inhibitory plasticity co-expression. We propose that these mechanisms of plasticity co-expression may be involved in maintaining excitation-inhibition balance and modulating neuronal integration modes.

Asunto(s)

Interneuronas , Plasticidad Neuronal , Células Piramidales , Animales , Plasticidad Neuronal/fisiología , Interneuronas/metabolismo , Células Piramidales/metabolismo , Células Piramidales/fisiología , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacología , Hipocampo/metabolismo , Hipocampo/fisiología , Parvalbúminas/metabolismo , Masculino , Ratones , Somatostatina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiología , Potenciación a Largo Plazo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética

RESUMEN

Insomnia is a common sleep disorder with significant societal and economic impacts. Current pharmacotherapies for insomnia are often accompanied by side effects, necessitating the development of new therapeutic drugs. In this study, the hypnotic effects and mechanisms of Sedum kamtschaticum 30% ethanol extract (ESK) and one of its active compounds, myricitrin, were investigated using pentobarbital-induced sleep experiments, immunohistochemistry (IHC), receptor binding assays, and enzyme-linked immunosorbent assay (ELISA). The pentobarbital-induced sleep experiments revealed that ESK and myricitrin reduced sleep latency and prolonged total sleep time in a dose-dependent manner. Based on c-Fos immunostaining, ESK, and myricitrin enhanced the GABAergic neural activity in sleep-promoting ventrolateral preoptic nucleus (VLPO) GABAergic. By measuring the level of GABA released from VLPO GABAergic neurons, ESK and myricitrin were found to increase GABA release in the hypothalamus. These effects were significantly inhibited by SCH. Moreover, ESK exhibited a concentration-dependent binding affinity for the adenosine A2A receptors (A2AR). In conclusion, ESK and myricitrin have hypnotic effects, and their underlying mechanisms may be related to the activation of A2AR.

Asunto(s)

Hipnóticos y Sedantes , Extractos Vegetales , Receptor de Adenosina A2A , Animales , Receptor de Adenosina A2A/metabolismo , Hipnóticos y Sedantes/farmacología , Ratones , Masculino , Extractos Vegetales/farmacología , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Pentobarbital/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Flavonoides/farmacología , Área Preóptica/efectos de los fármacos , Área Preóptica/metabolismo

RESUMEN

Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region that is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ in silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections' outputs on the GnRH pulse generator's activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity and offers insights into stress-related dysregulation.

Asunto(s)

Hormona Liberadora de Gonadotropina , Hormona Liberadora de Gonadotropina/metabolismo , Animales , Modelos Neurológicos , Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/metabolismo , Red Nerviosa/fisiología , Red Nerviosa/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Ratones , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo

RESUMEN

Escape behaviors help animals avoid harm from predators and other threats in the environment. Successful escape relies on integrating information from multiple stimulus modalities (of external or internal origin) to compute trajectories toward safe locations, choose between actions that satisfy competing motivations, and execute other strategies that ensure survival. To this end, escape behaviors must be adaptive. When a Drosophila melanogaster larva encounters a noxious stimulus, such as the focal pressure a parasitic wasp applies to the larval cuticle via its ovipositor, it initiates a characteristic escape response. The escape sequence consists of an initial abrupt bending, lateral rolling, and finally rapid crawling. Previous work has shown that the detection of noxious stimuli primarily relies on class IV multi-dendritic arborization neurons (Class IV neurons) located beneath the body wall, and more recent studies have identified several important components in the nociceptive neural circuitry involved in rolling. However, the neural mechanisms that underlie the rolling-escape sequence remain unclear. Here, we present both functional and anatomical evidence suggesting that bilateral descending neurons within the subesophageal zone of D. melanogaster larva play a crucial role in regulating the termination of rolling and subsequent transition to escape crawling. We demonstrate that these descending neurons (designated SeIN128) are inhibitory and receive inputs from a second-order interneuron upstream (Basin-2) and an ascending neuron downstream of Basin-2 (A00c). Together with optogenetic experiments showing that co-activation of SeIN128 neurons and Basin-2 influence the temporal dynamics of rolling, our findings collectively suggest that the ensemble of SeIN128, Basin-2, and A00c neurons forms a GABAergic feedback loop onto Basin-2, which inhibits rolling and thereby facilitates the shift to escape crawling.

Asunto(s)

Drosophila melanogaster , Reacción de Fuga , Neuronas GABAérgicas , Larva , Animales , Larva/fisiología , Neuronas GABAérgicas/fisiología , Reacción de Fuga/fisiología , Drosophila melanogaster/fisiología , Retroalimentación Fisiológica

RESUMEN

Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re → LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re → LS → LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.

Asunto(s)

Ansiedad , Neuronas GABAérgicas , Área Hipotalámica Lateral , Prurito , Animales , Ratones , Neuronas GABAérgicas/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Núcleos Talámicos de la Línea Media/metabolismo , Masculino , Conducta Animal , Vías Nerviosas , Plasticidad Neuronal , Núcleos Septales

RESUMEN

The hippocampus and medial entorhinal cortex (MEC) form a cognitive map that facilitates spatial navigation. As part of this map, MEC grid cells fire in a repeating hexagonal pattern across an environment. This grid pattern relies on inputs from the medial septum (MS). The MS, and specifically GABAergic neurons, are essential for theta rhythm oscillations in the entorhinal-hippocampal network; however, the role of this population in grid cell function is unclear. To investigate this, we use optogenetics to inhibit MS-GABAergic neurons and observe that MS-GABAergic inhibition disrupts grid cell spatial periodicity. Grid cell spatial periodicity is disrupted during both optogenetic inhibition periods and short inter-stimulus intervals. In contrast, longer inter-stimulus intervals allow for the recovery of grid cell spatial firing. In addition, grid cell phase precession is also disrupted. These findings highlight the critical role of MS-GABAergic neurons in maintaining grid cell spatial and temporal coding in the MEC.

Asunto(s)

Corteza Entorrinal , Neuronas GABAérgicas , Células de Red , Optogenética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Animales , Corteza Entorrinal/fisiología , Corteza Entorrinal/metabolismo , Corteza Entorrinal/citología , Células de Red/fisiología , Ratones , Masculino , Ritmo Teta/fisiología , Núcleos Septales/fisiología , Núcleos Septales/metabolismo

RESUMEN

Neurotrophins and their receptors are distinctly expressed during brain development and play crucial roles in the formation, survival, and function of neurons in the nervous system. Among these molecules, brain-derived neurotrophic factor (BDNF) has garnered significant attention due to its involvement in regulating GABAergic system development and function. In this review, we summarize and compare the expression patterns and roles of neurotrophins and their receptors in both the developing and adult brains of rodents, macaques, and humans. Then, we focus on the implications of BDNF in the development and function of GABAergic neurons from the cortex and the striatum, as both the presence of BDNF single nucleotide polymorphisms and disruptions in BDNF levels alter the excitatory/inhibitory balance in the brain. This imbalance has different implications in the pathogenesis of neurodevelopmental diseases like autism spectrum disorder (ASD), Rett syndrome (RTT), and schizophrenia (SCZ). Altogether, evidence shows that neurotrophins, especially BDNF, are essential for the development, maintenance, and function of the brain, and disruptions in their expression or signaling are common mechanisms in the pathophysiology of brain diseases.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo , Neuronas GABAérgicas , Humanos , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neuronas GABAérgicas/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Receptores de Factor de Crecimiento Nervioso/genética , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/genética , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/genética , Encéfalo/metabolismo , Encéfalo/crecimiento & desarrollo

RESUMEN

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, a transient population of injury-responsive neurons (iNeurons) show elevated plasticity 1 week post-injury. We found iNeurons are injury-surviving neurons that acquire a neuroblast-like gene expression signature after injury. CRISPR/Cas9 mutagenesis showed iNeurons are required for functional recovery and employ vesicular trafficking as an essential mechanism that underlies neuronal plasticity. This study provides a comprehensive resource of the cells and mechanisms that direct spinal cord regeneration and establishes zebrafish as a model of plasticity-driven neural repair.

Asunto(s)

Neurogénesis , Plasticidad Neuronal , Análisis de la Célula Individual , Traumatismos de la Médula Espinal , Regeneración de la Medula Espinal , Médula Espinal , Pez Cebra , Animales , Traumatismos de la Médula Espinal/metabolismo , Plasticidad Neuronal/fisiología , Neurogénesis/genética , Médula Espinal/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Sistemas CRISPR-Cas , Neuronas GABAérgicas/metabolismo , Recuperación de la Función , Modelos Animales de Enfermedad , Regeneración Nerviosa/fisiología , Animales Modificados Genéticamente

RESUMEN

Oxytocin affects social recognition, interactions, and behavior in adults. Despite growing data on the role of oxytocin in the sensory systems, its effects on early olfactory system development remain poorly understood. The present study aimed to investigate the developmental impact of oxytocin on selected parameters of the GABAergic system in olfactory brain regions. We found a significant increase in the expression of GABAergic markers and scaffolding proteins in the olfactory bulb during the early stages of development in both male and female rats, regardless of oxytocin treatment administered on postnatal days 2 and 3 (P2 and P3, 5 µg/pup). Oxytocin administration markedly reduced the expression of the scaffolding protein Gephyrin in male rats and it led to a significant increase in the number of GABAergic synaptic puncta in the piriform cortex of male rats at P5, P7, and P9. Our data suggest that the developmental action of oxytocin in relation to the GABAergic system may represent a mechanism by which the plasticity and maturation of olfactory brain regions are regulated.

Asunto(s)

Neuronas GABAérgicas , Proteínas de la Membrana , Bulbo Olfatorio , Oxitocina , Animales , Oxitocina/farmacología , Oxitocina/metabolismo , Femenino , Masculino , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/crecimiento & desarrollo , Proteínas de la Membrana/metabolismo , Ratas Wistar , Proteínas Portadoras/metabolismo , Ratas , Animales Recién Nacidos , Corteza Piriforme/efectos de los fármacos , Corteza Piriforme/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo

RESUMEN

Cotransmission, meaning the release of multiple neurotransmitters from one synapse, allows for increased diversity of signaling in the brain. Dopamine (DA) and γ-aminobutyric acid (GABA) are known to coexpress in many regions such as the olfactory bulb and the ventral tegmental area. Tuberoinfundibular dopaminergic neurons (TIDA) in the arcuate nucleus of the hypothalamus (Arc) project to the median eminence (ME) and regulate prolactin release from the pituitary, and prior work suggests dopaminergic Arc neurons also cotransmit GABA. However, the extent of cotransmission, and the projection patterns of these neurons have not been fully revealed. Here, we used a genetic intersectional reporter expression approach to selectively label cells that express both tyrosine hydroxylase (TH) and vesicular GABA transporter (VGAT). Through this approach, we identified cells capable of both DA and GABA cotransmission in the Arc, periventricular (Pe), paraventricular (Pa), ventromedial, and the dorsolateral hypothalamic nuclei, in addition to a novel population in the caudate putamen. The highest density of labeled cells was in the Arc, 6.68% of DAPI-labeled cells at Bregma -2.06 mm, and in the Pe, 2.83% of DAPI-labeled cells at Bregma -1.94 mm. Next, we evaluated the projections of these DA/GABA cells by injecting an mCherry virus that fluoresces in DA/GABA cells. We observed a cotransmitting DA/GABA population, with projections within the Arc, and to the Pa and ME. These data suggest DA/GABA Arc neurons are involved in prolactin release as a subset of TIDA neurons. Further investigation will elucidate the interactions of dopamine and GABA in the hypothalamus.NEW & NOTEWORTHY Cotransmitting dopaminergic (DA) and γ-aminobutyric acid (GABA)ergic (DA/GABA) neurons contribute to the complexity of neural circuits. Using a new genetic technique, we characterized the locations, density, and projections of hypothalamic DA/GABA neurons. DA/GABA cells are mostly in the arcuate nucleus (Arc), from which they project locally within the arcuate, to the median eminence (ME), and to the paraventricular (Pa) nucleus. There is also a small and previously unreported group of DA/GABA cells in the caudate putamen.

Asunto(s)

Núcleo Arqueado del Hipotálamo , Neuronas Dopaminérgicas , Neuronas GABAérgicas , Eminencia Media , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/citología , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Eminencia Media/metabolismo , Eminencia Media/citología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Masculino , Ratones , Tirosina 3-Monooxigenasa/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo , Femenino , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología

Asunto(s)

Neuronas GABAérgicas , Hormona Liberadora de Gonadotropina , Síndrome del Ovario Poliquístico , Receptores Androgénicos , Animales , Femenino , Humanos , Ratones , Neuronas GABAérgicas/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Receptores Androgénicos/metabolismo

RESUMEN

Dravet syndrome (DS) is a devastating early-onset refractory epilepsy syndrome caused by variants in the SCN1A gene. A disturbed GABAergic interneuron function is implicated in the progression to DS but the underlying developmental and pathophysiological mechanisms remain elusive, in particularly at the chromatin level. Induced pluripotent stem cells (iPSCs) derived from DS cases and healthy donors were used to model disease-associated epigenetic abnormalities of GABAergic development. Chromatin accessibility was assessed at multiple time points (Day 0, Day 19, Day 35, and Day 65) of GABAergic differentiation. Additionally, the effects of the commonly used anti-seizure drug valproic acid (VPA) on chromatin accessibility were elucidated in GABAergic cells. The distinct dynamics in the chromatin profile of DS iPSC predicted accelerated early GABAergic development, evident at D19, and diverged further from the pattern in control iPSC with continued differentiation, indicating a disrupted GABAergic maturation. Exposure to VPA at D65 reshaped the chromatin landscape at a variable extent in different iPSC-lines and rescued the observed dysfunctional development of some DS iPSC-GABA. The comprehensive investigation on the chromatin landscape of GABAergic differentiation in DS-patient iPSC offers valuable insights into the epigenetic dysregulations associated with interneuronal dysfunction in DS. Moreover, the detailed analysis of the chromatin changes induced by VPA in iPSC-GABA holds the potential to improve the development of personalized and targeted anti-epileptic therapies.

Asunto(s)

Diferenciación Celular , Epigénesis Genética , Epilepsias Mioclónicas , Neuronas GABAérgicas , Células Madre Pluripotentes Inducidas , Ácido Valproico , Células Madre Pluripotentes Inducidas/metabolismo , Humanos , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/metabolismo , Ácido Valproico/farmacología , Diferenciación Celular/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Cromatina/metabolismo , Canal de Sodio Activado por Voltaje NAV1.1/genética , Canal de Sodio Activado por Voltaje NAV1.1/metabolismo , Anticonvulsivantes/farmacología

RESUMEN

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.

Asunto(s)

Antidepresivos , Corteza Cerebral , Fluoxetina , Neuronas GABAérgicas , Proteínas de Homeodominio , Receptor trkB , Animales , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Receptor trkB/metabolismo , Receptor trkB/genética , Masculino , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/genética

RESUMEN

The subiculum is a key region of the brain involved in the initiation of pathological activity in temporal lobe epilepsy, and local GABAergic inhibition is essential to prevent subicular-originated epileptiform discharges. Subicular pyramidal cells may be easily distinguished into two classes based on their different firing patterns. Here, we have compared the strength of the GABAa receptor-mediated inhibitory postsynaptic currents received by regular- vs. burst-firing subicular neurons and their dynamic modulation by the activation of µ opioid receptors. We have taken advantage of the sequential re-patching of the same cell to initially classify pyramidal neurons according to their firing patters, and then to measure GABAergic events triggered by the optogenetic stimulation of parvalbumin- and somatostatin-expressing interneurons. Activation of parvalbumin-expressing cells generated larger responses in postsynaptic burst-firing neurons whereas the opposite was observed for currents evoked by the stimulation of somatostatin-expressing interneurons. In all cases, events depended critically on ω-agatoxin IVA- but not on ω-conotoxin GVIA-sensitive calcium channels. Optogenetic GABAergic input originating from both parvalbumin- and somatostatin-expressing cells was reduced in amplitude following the exposure to a µ opioid receptor agonist. The kinetics of this pharmacological sensitivity was different in regular- vs. burst-firing neurons, but only when responses were evoked by the activation of parvalbumin-expressing neurons, whereas no differences were observed when somatostatin-expressing cells were stimulated. In conclusion, our results show that a high degree of complexity regulates the organizing principles of subicular GABAergic inhibition, with the interaction of pre- and postsynaptic diversity at multiple levels. KEY POINTS: Optogenetic stimulation of parvalbumin- and somatostatin-expressing interneurons (PVs and SOMs) triggers inhibitory postsynaptic currents (IPSCs) in both regular- and burst-firing (RFs and BFs) subicular pyramidal cells. The amplitude of optogenetically evoked IPSCs from PVs (PV-opto IPSCs) is larger in BFs whereas IPSCs generated by the light activation of SOMs (SOM-opto IPSCs) are larger in RFs. Both PV- and SOM-opto IPSCs critically depend on ω-agatoxin IVA-sensitive P/Q type voltage-gated calcium channels, whereas no major effects are observed following exposure to ω-conotoxin GVIA, suggesting no significant involvement of N-type channels. The amplitude of both PV- and SOM-opto IPSCs is reduced by the probable pharmacological activation of presynaptic µ opioid receptors, with a faster kinetics of the effect observed in PV-opto IPSCs from RFs vs. BFs, but not in SOM-opto IPSCs. These results help us understand the complex interactions between different layers of diversity regulating GABAergic input onto subicular microcircuits.

Asunto(s)

Parvalbúminas , Células Piramidales , Somatostatina , Animales , Células Piramidales/fisiología , Ratones , Somatostatina/metabolismo , Parvalbúminas/metabolismo , Interneuronas/fisiología , Potenciales Postsinápticos Inhibidores , Masculino , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo , Hipocampo/fisiología , Hipocampo/citología , Optogenética , Receptores Opioides mu/metabolismo , Receptores Opioides mu/fisiología , Ratones Endogámicos C57BL , Femenino , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiología

RESUMEN

Engrams, which are cellular substrates of memory traces, have been identified in various brain areas, including the amygdala. While most identified engrams are composed of excitatory, glutamatergic neurons, GABAergic inhibitory engrams have been relatively overlooked. Here, we report the identification of an inhibitory engram in the central lateral amygdala (CeL), a key area for auditory fear conditioning. This engram is primarily composed of GABAergic somatostatin-expressing (SST(+)) and, to a lesser extent, protein kinase C-δ-expressing (PKC-δ(+)) neurons. Fear memory is accompanied by a preferential enhancement of synaptic inhibition onto PKC-δ(+) neurons. Silencing this CeL GABAergic engram disinhibits the activity of targeted extra-amygdaloid areas, selectively increasing the expression of fear. Our findings define the behavioral function of an engram formed exclusively by GABAergic inhibitory neurons in the mammalian brain.

Asunto(s)

Miedo , Neuronas GABAérgicas , Memoria , Somatostatina , Animales , Miedo/fisiología , Memoria/fisiología , Ratones , Neuronas GABAérgicas/metabolismo , Somatostatina/metabolismo , Proteína Quinasa C-delta/metabolismo , Masculino , Núcleo Amigdalino Central/metabolismo , Núcleo Amigdalino Central/fisiología , Ratones Endogámicos C57BL , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiología

RESUMEN

The nuclear receptors of thyroid hormone exert a broad influence on brain development and then on adult brain physiology. However, the cell-autonomous function of the receptors is combined with their indirect influence on cellular interactions. Mouse genetics allows one to distinguish between these 2 modes of action. It revealed that 1 of the main cell-autonomous functions of these receptors is to promote the maturation of GABAergic neurons. This review presents our current understanding of the action of thyroid hormone on this class of neurons, which are the main inhibitory neurons in most brain areas.

Asunto(s)

Neuronas GABAérgicas , Receptores de Hormona Tiroidea , Hormonas Tiroideas , Animales , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Receptores de Hormona Tiroidea/metabolismo , Receptores de Hormona Tiroidea/genética , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/fisiología , Humanos , Ratones , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo

RESUMEN

Based on the pathophysiological changes observed in schizophrenia, the gamma-aminobutyric acid (GABA) hypothesis may facilitate the development of targeted treatments for this disease. This hypothesis, mainly derived from postmortem brain results, postulates dysfunctions in a subset of GABAergic neurons, particularly parvalbumin-containing interneurons. In the cerebral cortex, the fast spike firing of parvalbumin-positive GABAergic interneurons is regulated by the Kv3.1 and Kv3.2 channels, which belong to a potassium channel subfamily. Decreased Kv3.1 levels have been observed in the prefrontal cortex of patients with schizophrenia, prompting the investigation of Kv3 channel modulators for the treatment of schizophrenia. However, biomarkers that capture the dysfunction of parvalbumin neurons are required for these modulators to be effective in the pharmacotherapy of schizophrenia. Electroencephalography and magnetoencephalography studies have demonstrated impairments in evoked gamma oscillations in patients with schizophrenia, which may reflect the dysfunction of cortical parvalbumin neurons. This review summarizes these topics and provides an overview of how the development of therapeutics that incorporate biomarkers could innovate the treatment of schizophrenia and potentially change the targets of pharmacotherapy.

Asunto(s)

Parvalbúminas , Esquizofrenia , Canales de Potasio Shaw , Esquizofrenia/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Humanos , Parvalbúminas/metabolismo , Canales de Potasio Shaw/metabolismo , Animales , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Interneuronas/metabolismo

RESUMEN

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here, we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels.

Asunto(s)

Segmento Inicial del Axón , Axones , Homeostasis , Plasticidad Neuronal , Sinapsis , Animales , Plasticidad Neuronal/fisiología , Segmento Inicial del Axón/metabolismo , Axones/fisiología , Axones/metabolismo , Ratones , Sinapsis/fisiología , Potenciales de Acción , Masculino , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo

RESUMEN

Huanglian Jiedu decoction (HLJD) has been used to treat ischemic stroke in clinic. However, the detailed protective mechanisms of HLJD on ischemic stroke have yet to be elucidated. The aim of this study is to elucidate the underlying pharmacological mechanisms of HLJD based on the inhibition of neuroinflammation and the amelioration of nerve cell damage. A middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats and received HLJD treatment. Effects of HLJD on neurological function was assessed based on Bederson's score, postural reflex test and asymmetry score. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining, Hematein and eosin (HE) and Nissl staining were used to observe the pathological changes in brain. Then, transcriptomics was used to screen the differential genes in brain tissue in MCAO/R model rats following HLJD intervention. Subsequently, the effects of HLJD on neutrophil extracellular trap (NET) formation-related neuroinflammation, gamma-aminobutyric acid (GABA)ergic synapse activation, nerve cell damage and proliferation were validated using immunofluorescence, western blot and enzyme-linked immunosorbent assay (ELISA). Our results showed that HLJD intervention reduced the Bederson's score, postural reflex test score and asymmetry score in MCAO/R model rats. Pathological staining indicated that HLJD treatment decreased the cerebral infarction area, mitigated neuronal damage and increased the numbers of Nissl bodies. Transcriptomics suggested that HLJD affected 435 genes in MCAO/R rats. Among them, several genes involving in NET formation and GABAergic synapses pathways were dysregulated. Subsequent experimental validation showed that HLJD reduced the MPO+CitH3+ positive expression area, reduced the protein expression of PAD4, p-P38/P38, p-ERK/ERK and decreased the levels of IL-1ß, IL-6 and TNF-α, reversed the increase of Iba1+TLR4+, Iba1+p65+ and Iba1+NLRP3+ positive expression area in brain. Moreover, HLJD increased GABA levels, elevated the protein expression of GABRG1 and GAT3, decreased the TUNEL positive expression area and increased the Ki67 positive expression area in brain. HLJD intervention exerts a multifaceted positive impact on ischemia-induced cerebral injury in MCAO/R rats. This intervention effectively inhibits neuroinflammation by mitigating NET formation, and concurrently improves nerve cell damage and fosters nerve cell proliferation through activating GABAergic synapses.

Asunto(s)

Isquemia Encefálica , Medicamentos Herbarios Chinos , Ratas Sprague-Dawley , Sinapsis , Animales , Medicamentos Herbarios Chinos/farmacología , Ratas , Masculino , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Modelos Animales de Enfermedad , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/complicaciones , Fármacos Neuroprotectores/farmacología , Encéfalo/patología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos

RESUMEN

Huntington's disease (HD) causes selective degeneration of striatal and cortical neurons, resulting in cell mosaicism of coexisting still functional and dysfunctional cells. The impact of non-cell autonomous mechanisms between these cellular states is poorly understood. Here we generated telencephalic organoids with healthy or HD cells, grown separately or as mosaics of the two genotypes. Single-cell RNA sequencing revealed neurodevelopmental abnormalities in the ventral fate acquisition of HD organoids, confirmed by cytoarchitectural and transcriptional defects leading to fewer GABAergic neurons, while dorsal populations showed milder phenotypes mainly in maturation trajectory. Healthy cells in mosaic organoids restored HD cell identity, trajectories, synaptic density, and communication pathways upon cell-cell contact, while showing no significant alterations when grown with HD cells. These findings highlight cell-type-specific alterations in HD and beneficial non-cell autonomous effects of healthy cells, emphasizing the therapeutic potential of modulating cell-cell communication in disease progression and treatment.

Asunto(s)

Enfermedad de Huntington , Organoides , Fenotipo , Telencéfalo , Enfermedad de Huntington/patología , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Organoides/patología , Organoides/metabolismo , Animales , Telencéfalo/patología , Telencéfalo/citología , Telencéfalo/metabolismo , Humanos , Ratones , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Análisis de la Célula Individual , Comunicación Celular , Mosaicismo , Neuronas/metabolismo , Neuronas/patología