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Background: Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility. Methods: Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV+ and PNN+ cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress. Results: Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV+ and PNN+ cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress. Conclusions: Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.
In this work, we aimed to go deeper into understanding perineuronal nets (PNNs), a specialized extracellular matrix that evolves and protects inhibitory neurons in the brain, specifically parvalbumin-positive interneurons (PVIs). PVIs are essential in regulating brain activity. PNNs only reach maturity in adulthood, which leaves these interneurons unprotected during early life. To investigate this vulnerability, we conducted experiments in which we exposed adolescent and adult animals to a stress protocol. We observed that adolescent animals exhibited a higher susceptibility to developing changes associated with psychiatric disorders later in life. This susceptibility may stem from the absence of PNN protection around their PVIs. To explore this possibility further, we administered an enzyme into a specific brain region, the ventral hippocampus, of adult animals to selectively remove PNNs and induce an adolescent-like state. When subjected to stress, these animals displayed abnormalities similar to those observed in animals stressed during adolescence. Our findings have significant implications, suggesting that the presence of PNN protection around PVIs may be critical for mitigating stress-related psychiatric disorders.
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Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individual's outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-κB dependent in VGluT2+ INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics.
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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.
Assuntos
Córtex Cerebral , Modelos Animais de Doenças , Hiperventilação , Deficiência Intelectual , Neurogênese , Fator de Transcrição 4 , Animais , Fator de Transcrição 4/metabolismo , Fator de Transcrição 4/genética , Feminino , Masculino , Camundongos , Hiperventilação/metabolismo , Hiperventilação/genética , Hiperventilação/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Fácies , Caracteres Sexuais , Interneurônios/metabolismo , Interneurônios/patologia , Células Piramidais/metabolismo , Células Piramidais/patologia , HaploinsuficiênciaRESUMO
BACKGROUND AND HYPOTHESIS: Redox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). A critical region particularly vulnerable to environmental insults during adolescence is the ventral hippocampus (vHip). However, the impact of severe stress on vHip redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood. STUDY DESIGN: After exposing adolescent animals to physical stress (postnatal day, PND31-40), we explored social and cognitive behaviors (PND47-49), the basal activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system, including mitochondrial respiratory function, reactive oxygen species (ROS) production, and glutathione (GSH) levels in the vHip and serum. STUDY RESULTS: Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on redox system- and synaptic-related genes. Stress impacted mitochondrial respiratory function and changes in ROS levels in the vHip. GSH and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress. CONCLUSIONS: Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ.
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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.
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Interneurônios , Parvalbuminas , Parvalbuminas/metabolismo , Interneurônios/metabolismo , Matriz Extracelular/metabolismo , Neurônios/metabolismo , Encéfalo/metabolismoRESUMO
The blockade of 5-HT6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT6 receptors with the specific agonist EMD 386088 (7.4 nM) or the antagonist SB-399885 (300 nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABAA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT6 receptor antagonists.
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Hipocampo , Receptores de Serotonina , Ratos , Animais , Ratos Wistar , Receptores de Serotonina/metabolismo , Células Piramidais/fisiologia , Transmissão Sináptica/fisiologia , Receptores de GABA-ARESUMO
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.
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Proteínas do Tecido Nervoso , Neurônios , Camundongos , Animais , Neurônios/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Interneurônios/fisiologia , Sinapses/fisiologia , Encéfalo/metabolismoRESUMO
Autism is a neurodevelopmental disorder with a neurobiological basis, characterized by a qualitative disturbance in social interaction and communication, associated with restricted interests and stereotyped behaviors. The genesis of autism cannot be interpreted through a single theory, and we can't compartmentalize brain areas as the only ones responsible for it. Among the neurobiological bases we can include: deficit in the social reward system, which generates poor social initiative; dysfunctions and disorders of the amygdala and the mirror neuron system, related to compromised empathy and social cognition; abnormalities in the minicolumns related to hyper-systematization; persistent inflammatory phenomena of the central nervous system related to microglia; alterations of neuropeptides such as oxytocin, vasopressin and cortisol, which compromise socialization, and neuronal inhibition disorders, expressed in GABAergic dysfunctions in interneurons, linked to autistic behaviors, epilepsy and sensory phenomena. Understanding the neurobiological bases of autism is complex and there is no single explanation or specific biological marker. However, identifying processes related to social cognition, molecular, inflammatory, neuromodulation mechanisms and bases linked to sensory disorders are fundamental elements.
El autismo es un trastorno del neurodesarrollo de base neurobiológica, caracterizado por una alteración cualitativa en la interacción social y la comunicación, asociado a intereses restringidos y conductas estereotipadas. La génesis del autismo no puede interpretarse a través de una sola teoría, tampoco podemos compartimentalizar áreas del cerebro como únicos responsables de la misma. Entre las bases neurobiológicas podemos incluir: déficit en el sistema de recompensa social, lo cual genera pobre iniciativa social; disfunciones y trastornos de la amígdala y el sistema de neuronas espejo, relacionadas al compromiso en la empatía y la cognición social; anormalidades en las minicolumnas relacionadas con la hiper-sistematización; fenómenos inflamatorios persistentes del sistema nervioso central relacionados a la microglía; alteraciones de los neuropéptidos como oxitocina, vasopresina y cortisol, que comprometen la socialización, y trastornos en la inhibición neuronal, expresados en disfunciones gabaérgicas en las inteneuronas, vinculadas a conductas autistas, epilepsia y fenómenos sensoriales. La comprensión de las bases neurobiológicas del autismo son complejas y no existe un marcador biológico específico. Sin embargo, identificar procesos relacionados a la cognición social, mecanismos moleculares, inflamatorios, de neuromodulación y bases vinculadas a trastornos sensoriales son elementos fundamentales.