ABSTRACT
BACKGROUND: Stress has become a common public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding the impact of stress considering critical variables, such as age, sex, and individual differences, is of the utmost importance for developing effective intervention strategies. METHODS: Stress effects (daily footshocks for 10 days) during adolescence (postnatal day [PND] 31-40) and adulthood (PND 65-74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex of male and female mice 5 weeks post stress. RESULTS: In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed decreased PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the prefrontal cortex. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. CONCLUSION: Our findings indicate that the timing of stress, sex, and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence.
Subject(s)
Behavior, Animal , Interneurons , Parvalbumins , Prefrontal Cortex , Stress, Psychological , Animals , Female , Male , Parvalbumins/metabolism , Interneurons/metabolism , Stress, Psychological/metabolism , Prefrontal Cortex/metabolism , Mice , Behavior, Animal/physiology , Sex Characteristics , Age Factors , Mice, Inbred C57BL , Social Behavior , Anxiety/metabolismABSTRACT
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.
Subject(s)
Cerebral Cortex , Disease Models, Animal , Hyperventilation , Intellectual Disability , Neurogenesis , Transcription Factor 4 , Animals , Transcription Factor 4/metabolism , Transcription Factor 4/genetics , Female , Male , Mice , Hyperventilation/metabolism , Hyperventilation/genetics , Hyperventilation/pathology , Intellectual Disability/genetics , Intellectual Disability/pathology , Intellectual Disability/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Facies , Sex Characteristics , Interneurons/metabolism , Interneurons/pathology , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , HaploinsufficiencyABSTRACT
The central amygdaloid nucleus (CeA) has an ancient phylogenetic development and functions relevant for animal survival. Local cells receive intrinsic amygdaloidal information that codes emotional stimuli of fear, integrate them, and send cortical and subcortical output projections that prompt rapid visceral and social behavior responses. We aimed to describe the morphology of the neurons that compose the human CeA (N = 8 adult men). Cells within CeA coronal borders were identified using the thionine staining and were further analyzed using the "single-section" Golgi method followed by open-source software procedures for two-dimensional and three-dimensional image reconstructions. Our results evidenced varied neuronal cell body features, number and thickness of primary shafts, dendritic branching patterns, and density and shape of dendritic spines. Based on these criteria, we propose the existence of 12 morphologically different spiny neurons in the human CeA and discuss the variability in the dendritic architecture within cellular types, including likely interneurons. Some dendritic shafts were long and straight, displayed few collaterals, and had planar radiation within the coronal neuropil volume. Most of the sampled neurons showed a few to moderate density of small stubby/wide spines. Long spines (thin and mushroom) were observed occasionally. These novel data address the synaptic processing and plasticity in the human CeA. Our morphological description can be combined with further transcriptomic, immunohistochemical, and electrophysiological/connectional approaches. It serves also to investigate how neurons are altered in neurological and psychiatric disorders with hindered emotional perception, in anxiety, following atrophy in schizophrenia, and along different stages of Alzheimer's disease.
Subject(s)
Central Amygdaloid Nucleus , Male , Adult , Animals , Humans , Phylogeny , Dendritic Spines/physiology , Neurons/physiology , InterneuronsABSTRACT
The brain extracellular matrix (ECM) has garnered increasing attention as a fundamental component of brain function in a predominantly "neuron-centric" paradigm. Particularly, the perineuronal nets (PNNs), a specialized net-like structure formed by ECM aggregates, play significant roles in brain development and physiology. PNNs enwrap synaptic junctions in various brain regions, precisely balancing new synaptic formation and long-term stabilization, and are highly dynamic entities that change in response to environmental stimuli, especially during the neurodevelopmental period. They are found mainly surrounding parvalbumin (PV)-expressing GABAergic interneurons, being proposed to promote PV interneuron maturation and protect them against oxidative stress and neurotoxic agents. This structural and functional proximity underscores the crucial role of PNNs in modulating PV interneuron function, which is critical for the excitatory/inhibitory balance and, consequently, higher-level behaviours. This review delves into the molecular underpinnings governing PNNs formation and degradation, elucidating their functional interactions with PV interneurons. In the broader physiological context and brain-related disorders, we also explore their intricate relationship with other molecules, such as reactive oxygen species and metalloproteinases, as well as glial cells. Additionally, we discuss potential therapeutic strategies for modulating PNNs in brain disorders.
Subject(s)
Interneurons , Parvalbumins , Parvalbumins/metabolism , Interneurons/metabolism , Extracellular Matrix/metabolism , Neurons/metabolism , Brain/metabolismABSTRACT
BACKGROUND: Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas. STUDY DESIGN: We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations. RESULTS: Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females. CONCLUSION: Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ.
Subject(s)
Schizophrenia , Humans , Mice , Male , Female , Animals , Schizophrenia/genetics , Parvalbumins/metabolism , Disease Models, Animal , Interneurons/metabolism , Prefrontal Cortex/metabolism , Hippocampus/metabolismABSTRACT
Abnormal dopamine neurotransmission is a common trait of some psychiatric diseases, like schizophrenia or bipolar disorder. Excessive dopaminergic tone in subcortical brain regions is associated with psychotic episodes, while reduced prefrontal dopaminergic activity is associated with impaired cognitive performance and reduced motivation, among other symptoms. Inhibitory interneurons expressing the calcium binding protein parvalbumin are particularly affected in both schizophrenia and bipolar disorder, as they set a fine-tuned physiological inhibitory/excitatory balance. Parvalbumin and somatostatin interneuron subtypes, are born from the medial ganglionic eminence and require the sequential expression of specific transcription factors for their specification, such as Nkx6.2. Here, we aimed at characterizing in detail interneuron subtypes derived from Nkx6.2 expressing progenitors by the generation of an Nkx6.2 Cre transgenic mouse line. We show that Nkx6.2 specifies over a third part of the total population of cortical somatostatin interneurons, preferentially at early developmental time points, whereas at late developmental stages, Nkx6.2 expressing progenitors shift to parvalbumin interneuron specification. Dopamine D2 receptor deletion from Nkx6.2 expressing progenitors causes abnormal phenotypes restricted to cognitive, motivation and anxiety domains. Our results show that Nkx6.2 have the potential to specify both somatostatin and parvalbumin interneurons in an opposite timed program and that DRD2 expression is required in Nkx6.2 expressing progenitors to avoid impaired phenotypes commonly associated to the pathophysiology of psychiatric diseases.
Subject(s)
Motivation , Parvalbumins , Animals , Mice , Anxiety/genetics , Cognition , Interneurons/metabolism , Mice, Transgenic , Parvalbumins/metabolism , Phenotype , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Somatostatin/genetics , Somatostatin/metabolismABSTRACT
Axons are equipped with the digital signaling capacity by which they generate and faithfully propagate action potentials (APs), and also with the analogue signaling capacity by which subthreshold activity in dendrites and soma is transmitted down the axon. Despite intense work, the extent and physiological role for subthreshold synaptic activity reaching the presynaptic boutons has remained elusive because of the technical limitation to record from them. To address this issue, we made simultaneous patch-clamp recordings from the presynaptic varicosities of cerebellar GABAergic interneurons together with their parent soma or postsynaptic target cells in young rat slices and/or primary cultures. Our tour-de-force direct functional dissection indicates that the somatodendritic spontaneous excitatory synaptic potentials are transmitted down the axon for significant distances, depolarizing presynaptic boutons. These analogously transmitted excitatory synaptic potentials augment presynaptic Ca++ influx upon arrival of an immediately following AP through a mechanism that involves a voltage-dependent priming of the Ca++ channels, leading to an increase in GABA release, without any modification in the presynaptic AP waveform or residual Ca++. Our work highlights the role of the axon in synaptic integration.
Subject(s)
Axons , Presynaptic Terminals , Rats , Animals , Axons/physiology , Presynaptic Terminals/physiology , Cerebellum/physiology , Action Potentials/physiology , Interneurons/physiology , gamma-Aminobutyric Acid , Synaptic Transmission/physiologyABSTRACT
Recent studies described 2-4 Hz oscillations in the hippocampus of rats performing stationary locomotion on treadmills and other apparatus. Since the 2-4 Hz rhythm shares common features with theta (5-12 Hz) oscillations-such as a positive amplitude-running speed relationship and modulation of spiking activity-many have questioned whether these rhythms are related or independently generated. Here, we analyzed local field potentials and spiking activity from the dorsal CA1 of rats executing a spatial alternation task and running for ~15 s in a wheel during the intertrial intervals both before and after muscimol injection into the medial septum. We observed remarkable 4-Hz oscillations during wheel runs, which presented amplitude positively correlated with running speed. Surprisingly, the amplitude of 4-Hz and theta oscillations were inversely related. Medial septum inactivation abolished hippocampal theta but preserved 4-Hz oscillations. It also affected the entrainment of pyramidal cells and interneurons by 4-Hz rhythmic activity. In all, these results dissociate the underlying mechanism of 4-Hz and theta oscillations in the rat hippocampus.
Subject(s)
Hippocampus , Theta Rhythm , Rats , Animals , Theta Rhythm/physiology , Hippocampus/physiology , Pyramidal Cells/physiology , Locomotion , Interneurons/physiologyABSTRACT
GABAergic inhibition is critical for the precision of neuronal spiking and the homeostatic regulation of network activity in the brain. Adult neurogenesis challenges network homeostasis because new granule cells (GCs) integrate continuously in the functional dentate gyrus. While developing, adult-born GCs undergo a transient state of enhanced excitability due to the delayed maturation of perisomatic GABAergic inhibition by parvalbumin interneurons (PV-INs). The mechanisms underlying this delayed synaptic maturation remain unknown. We examined the morphology and function of synapses formed by PV-INs onto new GCs over a 2-month interval in young adult mice, and investigated the influence of the synaptic adhesion molecule neuroligin-2 (NL2). Perisomatic appositions of PV-IN terminals onto new GCs were conspicuous at 2 weeks and continued to grow in size to reach a plateau over the fourth week. Postsynaptic knockdown of NL2 by expression of a short-hairpin RNA (shNL2) in new GCs resulted in smaller size of synaptic contacts, reduced area of perisomatic appositions of the vesicular GABA transporter VGAT, and the number of presynaptic active sites. GCs expressing shNL2 displayed spontaneous GABAergic responses with decreased frequency and amplitude, as well as slower kinetics compared to control GCs. In addition, postsynaptic responses evoked by optogenetic stimulation of PV-INs exhibited slow kinetics, increased paired-pulse ratio and coefficient of variation in GCs with NL2 knockdown, suggesting a reduction in the number of active synapses as well as in the probability of neurotransmitter release (Pr ). Our results demonstrate that synapses formed by PV-INs on adult-born GCs continue to develop beyond the point of anatomical growth, and require NL2 for the structural and functional maturation that accompanies the conversion into fast GABAergic transmission.
Subject(s)
Nerve Tissue Proteins , Neurons , Mice , Animals , Neurons/physiology , Nerve Tissue Proteins/metabolism , Cell Adhesion Molecules, Neuronal/genetics , Cell Adhesion Molecules, Neuronal/metabolism , Interneurons/physiology , Synapses/physiology , Brain/metabolismABSTRACT
Esta revisión busca proporcionar a los profesionales de la salud una mayor comprensión del dolor para su actividad clínica-asistencial. Basados en la hipóte-sis de neuroplasticidad presentada inicialmente por Ramón y Cajal y la teoría de la compuerta en la vía dolorosa presentada por Melzack y Wall, se ha ela-borado una revisión bibliográfica con el objetivo de abordar la modulación de la vía nociceptiva desde un punto de vista fisiopatológico. Asimismo, se presen-tan los principales resultados obtenidos durante los últimos años en nuestro laboratorio usando ratas Wistar hembras como modelo de dolor experimental. Finalmente, se describe un circuito original de modu-lación central a nivel del subnúcleo caudal del trigé-mino con una visión integral de los componentes del sistema nociceptivo orofacial, para ayudar al clínico a comprender situaciones de sensibilización central con perpetuación del dolor y cómo paulatinamente el sistema nervioso central pone en marcha un sistema de modulación para adaptarse y alcanzar un estado similar al basal (AU)
This review aims to provide health professionals with a better understanding of pain for their clinical-care activity. Based on the neuroplasticity hypothesis initially presented by Ramón and Cajal, and the gate theory in the pain pathway presented by Melzack and Wall, a literature review has been carried out with the aim of addressing the modulation of the nociceptive pathway from a pathophysiological point of view. The main results obtained in recent years in our laboratory using female Wistar rats as an experimental pain model are also presented. Finally, an original central modulation circuit at the level of the caudal trigeminal subnucleus is described with a comprehensive view of the components of the orofacial nociceptive system, to help the clinician to understand situations of central sensitization with perpetuation of pain and how the central nervous system gradually sets in motion a modulation system to adapt and reach a state similar to the basal one (AU)
Subject(s)
Humans , Animals , Rats , Pain/physiopathology , Central Nervous System/physiology , Nociception/physiology , Neuronal Plasticity/physiology , Astrocytes , Rats, Wistar , Hyperalgesia/physiopathology , InterneuronsABSTRACT
Significant progress has been made in elucidating the basic principles that govern neuronal specification in the developing central nervous system. In contrast, much less is known about the origin of astrocytic diversity. Here, we demonstrate that a restricted pool of progenitors in the mouse spinal cord, expressing the transcription factor Dbx1, produces a subset of astrocytes, in addition to interneurons. Ventral p0-derived astrocytes (vA0 cells) exclusively populate intermediate regions of spinal cord with extraordinary precision. The postnatal vA0 population comprises gray matter protoplasmic and white matter fibrous astrocytes and a group of cells with strict radial morphology contacting the pia. We identified that vA0 cells in the lateral funiculus are distinguished by the expression of reelin and Kcnmb4. We show that Dbx1 mutants have an increased number of vA0 cells at the expense of p0-derived interneurons. Manipulation of the Notch pathway, together with the alteration in their ligands seen in Dbx1 knockouts, suggest that Dbx1 controls neuron-glial balance by modulating Notch-dependent cell interactions. In summary, this study highlights that restricted progenitors in the dorsal-ventral neural tube produce region-specific astrocytic subgroups and that progenitor transcriptional programs highly influence glial fate and are instrumental in creating astrocyte diversity.
Subject(s)
Astrocytes , Spinal Cord , Animals , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Interneurons/metabolism , Large-Conductance Calcium-Activated Potassium Channel beta Subunits/metabolism , Mice , Neuroglia/metabolism , Signal Transduction/genetics , Spinal Cord/metabolismABSTRACT
BACKGROUND: In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating and therapeutic options become scarce. Aberrant activity of striatal cholinergic interneurons (SCIN) has been shown to be critical to PD and dyskinesia, but the systemic administration of cholinergic medications can exacerbate extrastriatal-related symptoms. Thus, targeting the mechanisms causing pathological SCIN activity in severe PD with motor fluctuations and dyskinesia is a promising therapeutic alternative. METHODS: We used ex vivo electrophysiological recordings combined with pharmacology to study the alterations in intracellular signaling that contribute to the altered SCIN physiology observed in the 6-hydroxydopamine mouse model of PD treated with levodopa. RESULTS: The altered phenotypes of SCIN of parkinsonian mice during the "off levodopa" state resulting from aberrant Kir/leak and Kv1.3 currents can be rapidly reverted by acute inhibition of cAMP-ERK1/2 signaling. Inverse agonists that inhibit the ligand-independent activity of D5 receptors, like clozapine, restore Kv1.3 and Kir/leak currents and SCIN normal physiology in dyskinetic mice. CONCLUSION: Our work unravels a signaling pathway involved in the dysregulation of membrane currents causing SCIN hyperexcitability and burst-pause activity in parkinsonian mice treated with levodopa (l-dopa). These changes persist during off-medication periods due to tonic mechanisms that can be acutely reversed by pharmacological interventions. Thus, targeting the D5-cAMP-ERK1/2 signaling pathway selectively in SCIN may have therapeutic effects in PD and dyskinesia by restoring the normal SCIN function. © 2022 International Parkinson and Movement Disorder Society.
Subject(s)
Dyskinesia, Drug-Induced , Parkinson Disease , Animals , Antiparkinson Agents/pharmacology , Antiparkinson Agents/therapeutic use , Cholinergic Agents/metabolism , Cholinergic Agents/pharmacology , Cholinergic Agents/therapeutic use , Corpus Striatum/metabolism , Disease Models, Animal , Dyskinesia, Drug-Induced/pathology , Interneurons/metabolism , Levodopa/pharmacology , Levodopa/therapeutic use , Mice , Oxidopamine/toxicityABSTRACT
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by several alterations, including disorganized brain cytoarchitecture and excitatory/inhibitory (E/I) imbalance. We aimed to analyze aspects associated with the inhibitory components in ASD, using bioinformatics to develop notions about embryonic life and tissue analysis for postnatal life. We analyzed microarray and RNAseq datasets of embryos from different ASD models, demonstrating that regions involved in neuronal development are affected. We evaluated the effect of prenatal treatment with resveratrol (RSV) on the neuronal organization and quantity of parvalbumin-positive (PV+), somatostatin-positive (SOM+), and calbindin-positive (CB+) GABAergic interneurons, besides the levels of synaptic proteins and GABA receptors in the medial prefrontal cortex (mPFC) and hippocampus (HC) of the ASD model induced by valproic acid (VPA). VPA increased the total number of neurons in the mPFC, while it reduced the number of SOM+ neurons, as well as the proportion of SOM+, PV+, and CB+ neurons (subregion-specific manner), with preventive effects of RSV. In summary, metabolic alterations or gene expression impairments could be induced by VPA, leading to extensive damage in the late developmental stages. By contrast, due to its antioxidant, neuroprotective, and opposite action on histone properties, RSV may avoid damages induced by VPA.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Prenatal Exposure Delayed Effects , Resveratrol , Valproic Acid , Animals , Autism Spectrum Disorder/metabolism , Autistic Disorder/chemically induced , Autistic Disorder/drug therapy , Autistic Disorder/genetics , Disease Models, Animal , Female , Interneurons/metabolism , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Rats , Resveratrol/therapeutic use , Valproic Acid/adverse effectsABSTRACT
How do animals adopt a given behavioral strategy to solve a recurrent problem when several effective strategies are available to reach the goal? Here we provide evidence that striatal cholinergic interneurons (SCINs) modulate their activity when mice must select between different strategies with similar goal-reaching effectiveness. Using a cell type-specific transgenic murine system, we show that adult SCIN ablation impairs strategy selection in navigational tasks where a goal can be independently achieved by adopting an allocentric or egocentric strategy. SCIN-depleted mice learn to achieve the goal in these tasks, regardless of their appetitive or aversive nature, in a similar way as controls. However, they cannot shift away from their initially adopted strategies, as control mice do, as training progresses. Our results indicate that SCINs are required for shaping the probability function used for strategy selection as experience accumulates throughout training. Thus, SCINs may be critical for the resolution of cognitive conflicts emerging when several strategies compete for behavioral control while adapting to environmental demands. Our findings may increase our understanding about the emergence of perseverative/compulsive traits in neuropsychiatric disorders with a reported SCIN reduction, such as Tourette and Williams syndromes.SIGNIFICANCE STATEMENT Selecting the best suited strategy to solve a problem is vital. Accordingly, available strategies must be compared across multiple dimensions, such as goal attainment effectiveness, cost-benefit trade-off, and cognitive load. The striatum is involved in strategy selection when strategies clearly diverge in their goal attainment capacity; however, its role whenever several strategies can be used for goal reaching-therefore making selection dependent on additional strategy dimensions-remains poorly understood. Here, we show that striatal cholinergic interneurons can signal strategy competition. Furthermore, they are required to adopt a given strategy whenever strategies with similar goal attainment capacity compete for behavioral control. Our study suggests that striatal cholinergic dysfunction may result in anomalous resolution of problems whenever complex cognitive valuations are required.
Subject(s)
Cholinergic Neurons/physiology , Corpus Striatum/physiology , Interneurons/physiology , Problem Solving/physiology , Spatial Navigation/physiology , Animals , Male , Mice , Mice, Inbred C57BLABSTRACT
Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.
Subject(s)
Brain Waves/physiology , Electrophysiological Phenomena/physiology , Hippocampus/physiopathology , Interneurons/physiology , Nerve Net/physiopathology , Prefrontal Cortex/physiopathology , Pyramidal Cells/physiology , Receptors, N-Methyl-D-Aspartate/deficiency , Schizophrenia/physiopathology , Age Factors , Animals , Disease Models, Animal , Hippocampus/metabolism , Interneurons/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Net/metabolism , Parvalbumins/metabolism , Prefrontal Cortex/metabolism , Pyramidal Cells/metabolism , Schizophrenia/metabolismABSTRACT
Neurogenesis is a powerful mechanism for structural and functional remodeling that occurs in restricted areas of the adult brain. Although different neurotransmitters regulate various aspects of the progression from neural stem cell quiescence to neuronal maturation, GABA is the main player. The developmental switch from excitation to inhibition combined with a heterogeneous population of GABAergic interneurons that target different subcellular compartments provides multiple points for the regulation of development and function of new neurons. This complexity is enhanced by feedback and feedforward networks that act as sensors and controllers of circuit activity, impinging directly or indirectly onto developing granule cells and, subsequently, on mature neurons. Newly generated granule cells ultimately connect with input and output partners in a manner that is largely sculpted by the activity of local circuits.
Subject(s)
Neural Stem Cells , Neurons , GABAergic Neurons , Hippocampus , Interneurons , NeurogenesisABSTRACT
Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Ion Channels/metabolism , alpha7 Nicotinic Acetylcholine Receptor/chemistry , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Antidepressive Agents/classification , Choline/pharmacology , Interneurons/drug effects , Interneurons/metabolism , Ion Channel Gating/drug effects , Molecular Docking Simulation , Molecular Dynamics Simulation , Rats , Structural Homology, Protein , Structure-Activity Relationship , ThermodynamicsABSTRACT
Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although whole-brain computational models have reproduced this neuromodulatory effect, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, we introduce a local inhibitory feedback as a plausible biophysical mechanism that enables the integration of whole-brain activity, and that interacts with the other neuromodulatory influences to facilitate the transition between different functional segregation/integration regimes in the brain.
Subject(s)
Brain/physiology , Connectome , Models, Neurological , Biophysical Phenomena , Brain/diagnostic imaging , Cholinergic Neurons/physiology , Computational Biology , Computer Simulation , Electroencephalography , Feedback, Physiological , Humans , Interneurons/physiology , Magnetic Resonance Imaging , Nerve Net/diagnostic imaging , Nerve Net/physiology , Neural Pathways/diagnostic imaging , Neural Pathways/physiology , Neurotransmitter Agents/physiologyABSTRACT
BACKGROUND: Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa-induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal-related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets. METHODS: We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6-hydroxydopamine mouse model of PD treated with levodopa. RESULTS: Cholinergic interneurons exhibit pathological burst-pause activity in the parkinsonian "off levodopa" state. This is mediated by a persistent ligand-independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward-rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst-pause firing. CONCLUSION: Our data unravel a mechanism causing aberrant cholinergic interneuron burst-pause activity in parkinsonian mice treated with levodopa. Targeting D5-cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function. © 2021 International Parkinson and Movement Disorder Society.