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1.
Int J Neuropsychopharmacol ; 27(2)2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38175142

RESUMEN

BACKGROUND: Cannabis use is a risk factor of psychiatric illness, such as bipolar disorder type-I (BDI). Indeed, cannabis use strongly influences the onset and clinical course of BDI, although the biological mechanisms underlying this interaction remain unknown. Therefore, we have reviewed the biological mechanisms affected by cannabis use that may trigger BD. METHODS: A systematic review was carried out of articles in which gene expression was studied in cannabis users or human-derived cells exposed to tetrahydrocannabinol (THC) or cannabidiol (CBD). A second systematic review was then performed to identify articles in which gene expression was studied in BDI samples, highlighting those that described alterations to the same molecular and cellular mechanisms affected by cannabis/THC/CBD. RESULTS: The initial search identified 82 studies on cannabis and 962 on BDI. After removing duplicates and applying the inclusion/exclusion criteria, 9 studies into cannabis and 228 on BDI were retained. The molecular and cellular mechanisms altered by cannabis use or THC/CBD exposure were then identified, including neural development and function, cytoskeletal function, cell adhesion, mitochondrial biology, inflammatory related pathways, lipid metabolism, the endocannabinoid system, the hypocretin/orexin system, and apoptosis. Alterations to those activities were also described in 19 of 228 focused on BDI. CONCLUSIONS: The biological mechanisms described in this study may be good candidates to the search for diagnostic biomarkers and therapeutic targets for BDI. Because cannabis use can trigger the onset of BD, further studies would be of interest to determine whether they are involved in the early development of the disorder, prompting early treatment.


Asunto(s)
Trastorno Bipolar , Cannabidiol , Cannabis , Alucinógenos , Humanos , Trastorno Bipolar/tratamiento farmacológico , Agonistas de Receptores de Cannabinoides , Cannabidiol/farmacología , Alucinógenos/uso terapéutico , Factores de Riesgo , Dronabinol/efectos adversos
2.
Cereb Cortex ; 21(5): 1028-41, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-20843898

RESUMEN

Principal neurons in the adult cerebral cortex undergo synaptic, dendritic, and spine remodeling in response to different stimuli, and several reports have demonstrated that the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) participates in these plastic processes. However, there is only limited information on the expression of this molecule on interneurons and on its role in the structural plasticity of these cells. We have found that PSA-NCAM is expressed in mature interneurons widely distributed in all the extension of the cerebral cortex and have excluded the expression of this molecule in most principal cells. Although PSA-NCAM expression is generally considered a marker of immature neurons, birth-dating analyses reveal that these interneurons do not have an adult or perinatal origin and that they are generated during embryonic development. PSA-NCAM expressing interneurons show reduced density of perisomatic and peridendritic puncta expressing different synaptic markers and receive less perisomatic synapses, when compared with interneurons lacking this molecule. Moreover, they have reduced dendritic arborization and spine density. These data indicate that PSA-NCAM expression is important for the connectivity of interneurons in the adult cerebral cortex and that its regulation may play an important role in the structural plasticity of inhibitory networks.


Asunto(s)
Diferenciación Celular/genética , Corteza Cerebral/metabolismo , Interneuronas/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/genética , Inhibición Neural/genética , Ácidos Siálicos/genética , Animales , Forma de la Célula/genética , Corteza Cerebral/patología , Interneuronas/patología , Masculino , Molécula L1 de Adhesión de Célula Nerviosa/biosíntesis , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Neurogénesis/genética , Plasticidad Neuronal/genética , Ratas , Ratas Sprague-Dawley , Ácidos Siálicos/biosíntesis
3.
Neurobiol Stress ; 19: 100460, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35734023

RESUMEN

This manuscript is dedicated to the memory of Bruce S. McEwen, to commemorate the impact he had on how we understand stress and neuronal plasticity, and the profound influence he exerted on our scientific careers. The focus of this review is the impact of stressors on inhibitory circuits, particularly those of the limbic system, but we also consider other regions affected by these adverse experiences. We revise the effects of acute and chronic stress during different stages of development and lifespan, taking into account the influence of the sex of the animals. We review first the influence of stress on the physiology of inhibitory neurons and on the expression of molecules related directly to GABAergic neurotransmission, and then focus on specific interneuron subpopulations, particularly on parvalbumin and somatostatin expressing cells. Then we analyze the effects of stress on molecules and structures related to the plasticity of inhibitory neurons: the polysialylated form of the neural cell adhesion molecule and perineuronal nets. Finally, we review the potential of antidepressants or environmental manipulations to revert the effects of stress on inhibitory circuits.

4.
Transl Psychiatry ; 10(1): 177, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32488050

RESUMEN

The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.


Asunto(s)
Dronabinol , Receptores de N-Metil-D-Aspartato , Adolescente , Adulto , Animales , Dronabinol/farmacología , Humanos , Interneuronas/metabolismo , Ratones , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Aislamiento Social
5.
eNeuro ; 4(2)2017.
Artículo en Inglés | MEDLINE | ID: mdl-28466069

RESUMEN

The exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, especially in the prefrontal cortex and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fluorescent excitatory and inhibitory neurons, received a single injection of MK801 (NMDAR antagonist) or vehicle solution at postnatal day 7 and/or were socially isolated from the age of weaning until adulthood (3 months old). We found that anxiety-related behavior, brain volume, neuronal structure, and the expression of molecules related to plasticity and E/I neurotransmission in adult mice were importantly affected by early-life stress. Interestingly, many of these effects were potentiated when the stress paradigm was applied to mice perinatally injected with MK801 ("double-hit" model). These results clearly show the impact of early-life stress on the adult brain, especially on the structure and plasticity of inhibitory networks, and highlight the double-hit model as a valuable tool to study the contribution of early-life stress in the emergence of neurodevelopmental psychiatric disorders, such as schizophrenia.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Aislamiento Social/psicología , Amígdala del Cerebelo/metabolismo , Animales , Maleato de Dizocilpina/farmacología , Ratones Transgénicos , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/fisiología , Sinaptofisina/metabolismo
6.
Neurosci Lett ; 613: 41-6, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26733301

RESUMEN

The adult brain retains a substantial capacity for synaptic reorganization, which includes a wide range of modifications from molecular to structural plasticity. Previous reports have demonstrated that the structural remodeling of excitatory neurons seems to occur in parallel to changes in GABAergic neurotransmission. The function of neuronal inhibitory networks can be modified through GABAA receptors, which have a binding site for benzodiazepines (BZ). Although BZs are among the most prescribed drugs, is not known whether they modify the structure and connectivity of pyramidal neurons. In the present study we wish to elucidate the impact of a chronic treatment of 21 days with diazepam (2mg/kg, ip), a BZ that acts as an agonist of GABAA receptors, on the structural plasticity of pyramidal neurons in the prefrontal cortex of adult mice. We have examined the density of dendritic spines and the density of axonal en passant boutons in the cingulate cortex. Although no significant changes were observed in their anxiety levels, animals treated with diazepam showed a decrease in the density of spines in the apical dendrites of pyramidal neurons. Most GFP-expressing en passant boutons in the upper layers of the cingulate cortex had an extracortical origin and no changes in their density were detected after diazepam treatment. These results indicate that the chronic potentiation of GABAergic synapses can induce the structural remodeling of postsynaptic elements in pyramidal neurons.


Asunto(s)
Espinas Dendríticas/efectos de los fármacos , Diazepam/efectos adversos , Agonistas de Receptores de GABA-A/efectos adversos , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Espinas Dendríticas/ultraestructura , Relación Dosis-Respuesta a Droga , Masculino , Ratones Transgénicos , Corteza Prefrontal/ultraestructura , Células Piramidales/ultraestructura
7.
Neuropsychopharmacology ; 41(3): 751-61, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26152839

RESUMEN

Emerging evidence indicates that attention deficits, which are frequently observed as core symptoms of neuropsychiatric disorders, may be elicited by early life stress. However, the mechanisms mediating these stress effects remain unknown. The prefrontal cortex (PFC) has been implicated in the regulation of attention, including dysfunctions in GABAergic transmission, and it is highly sensitive to stress. Here, we investigated the involvement of neuroligin-2 (NLGN-2), a synaptic cell adhesion molecule involved in the stabilization and maturation of GABAergic synapses, in the PFC in the link between stress and attention deficits. First, we established that exposure of rats to stress during the peripubertal period impairs attention in the five-choice serial reaction time task and results in reductions in the GABA-synthesizing enzyme glutamic acid decarboxylase in different PFC subregions (ie, prelimbic (PL), infralimbic, and medial and ventral orbitofrontal (OFC) cortex) and in NLGN-2 in the PL cortex. In peripubertally stressed animals, NLGN-2 expression in the PL and OFC cortex correlated with attention measurements. Subsequently, we found that adeno-associated virus-induced rescue of NLGN-2 in the PFC reverses the stress-induced attention deficits regarding omitted trials. Therefore, our findings highlight peripuberty as a period that is highly vulnerable to stress, leading to the development of attention deficits and a dysfunction in the PFC GABAergic system and NLGN-2 expression. Furthermore, NLGN-2 is underscored as a promising target to treat stress-induced cognitive alterations, and in particular attentional deficits as manifested by augmented omissions in a continuous performance task.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Atención/fisiología , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Estrés Psicológico/metabolismo , Animales , Trastorno por Déficit de Atención con Hiperactividad/etiología , Moléculas de Adhesión Celular Neuronal/genética , Dependovirus , Modelos Animales de Enfermedad , Vectores Genéticos , Inmunohistoquímica , Masculino , Proteínas del Tejido Nervioso/genética , Pruebas Neuropsicológicas , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Wistar , Maduración Sexual/fisiología , Estrés Psicológico/complicaciones , Ácido gamma-Aminobutírico/metabolismo
8.
PLoS One ; 9(4): e94666, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24736324

RESUMEN

Stress during childhood and adolescence is a risk factor for psychopathology. Alterations in γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, have been found following stress exposure and fear experiences and are often implicated in anxiety and mood disorders. Abnormal amygdala functioning has also been detected following stress exposure and is also implicated in anxiety and social disorders. However, the amygdala is not a unitary structure; it includes several nuclei with different functions and little is known on the potential differences the impact of early life stress may have on this system within different amygdaloid nuclei. We aimed here to evaluate potential regional differences in the expression of GABAergic-related markers across several amygdaloid nuclei in adult rats subjected to a peripuberty stress protocol that leads to enhanced basal amygdala activity and psychopathological behaviors. More specifically, we investigated the protein expression levels of glutamic acid decarboxylase (GAD; the principal synthesizing enzyme of GABA) and of GABA-A receptor subunits α2 and α3. We found reduced GAD and GABA-A α3, but not α2, subunit protein levels throughout all the amygdala nuclei examined (lateral, basolateral, basomedial, medial and central) and increased anxiety-like behaviors and reduced sociability in peripubertally stressed animals. Our results identify an enduring inhibition of the GABAergic system across the amygdala following exposure to early adversity. They also highlight the suitability of the peripuberty stress model to investigate the link between treatments targeting the dysfunctional GABAergic system in specific amygdala nuclei and recovery of specific stress-induced behavioral dysfunctions.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Conducta Animal , Pubertad/psicología , Estrés Psicológico/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Ansiedad/psicología , Peso Corporal , Conducta Exploratoria , Glutamato Descarboxilasa/metabolismo , Relaciones Interpersonales , Pubertad/metabolismo , Ratas , Ratas Wistar , Receptores de GABA-A/metabolismo , Estrés Psicológico/psicología
9.
Neuropsychopharmacology ; 39(5): 1148-58, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24213355

RESUMEN

Neuroligins (NLGNs) are cell adhesion molecules that are important for proper synaptic formation and functioning, and are critical regulators of the balance between neural excitation/inhibition (E/I). Mutations in NLGNs have been linked to psychiatric disorders in humans involving social dysfunction and are related to similar abnormalities in animal models. Chronic stress increases the likelihood for affective disorders and has been shown to induce changes in neural structure and function in different brain regions, with the hippocampus being highly vulnerable to stress. Previous studies have shown evidence of chronic stress-induced changes in the neural E/I balance in the hippocampus. Therefore, we hypothesized that chronic restraint stress would lead to reduced hippocampal NLGN-2 levels, in association with alterations in social behavior. We found that rats submitted to chronic restraint stress in adulthood display reduced sociability and increased aggression. This occurs along with a reduction of NLGN-2, but not NLGN-1 expression (as shown with western blot, immunohistochemistry, and electron microscopy analyses), throughout the hippocampus and detectable in different layers of the CA1, CA3, and DG subfields. Furthermore, using synthetic peptides that comprise sequences in either NLGN-1 (neurolide-1) or NLGN-2 (neurolide-2) involved in the interaction with their presynaptic partner neurexin (NRXN)-1, intra-hippocampal administration of neurolide-2 led also to reduced sociability and increased aggression. These results highlight hippocampal NLGN-2 as a key molecular substrate regulating social behaviors and underscore NLGNs as promising targets for the development of novel drugs for the treatment of dysfunctional social behaviors.


Asunto(s)
Agresión/fisiología , Moléculas de Adhesión Celular Neuronal/metabolismo , Hipocampo/fisiopatología , Proteínas del Tejido Nervioso/metabolismo , Conducta Social , Estrés Psicológico/fisiopatología , Animales , Moléculas de Adhesión Celular Neuronal/genética , Células Cultivadas , Enfermedad Crónica , Corticosterona/sangre , Hipocampo/patología , Masculino , Proteínas del Tejido Nervioso/genética , Neuritas/fisiología , Neuronas/fisiología , Tamaño de los Órganos , Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Superficie Celular/metabolismo , Restricción Física , Estrés Psicológico/patología
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