JUVENILE ABLATION OF EXCITATORY AND INHIBITORY NEURONS IN THE VENTRAL HIPPOCAMPUS OF MICE LEAD TO DISSOCIABLE SCHIZOPHRENIA- RELEVANT PHENOTYPES AT YOUNG ADULTHOOD
Notice bibliographique
Résumé
Abstract Background Developmental hippocampal abnormalities have been postulated to be important drivers of cognitive and behavioral anomalies in schizophrenia. The ventral hippocampus (VH) strongly influences behaviors of relevance to schizophrenia. Based on the reported deficits in excitatory and inhibitory neurons in the anterior hippocampus (VH in rodents) of individuals with schizophrenia, we hypothesized that an early developmental interruption of excitatory/inhibitory balance in the VH may be a mechanism by which hippocampal abnormalities lead to adult schizophrenia-related phenotypes. Aims & Objectives We investigated the behavioral and neural consequences of the ablation of excitatory (glutamatergic) or inhibitory (parvalbumin, PV) neurons in the mouse VH during juvenile ages. Behaviors of male and female mice were studied at young adult ages after diphtheria toxin A (DTA)-induced ablation of excitatory and PV neurons. PFC local circuit transmission as well as microglial properties were examined as possible mechanisms driving the behavioral changes after juvenile VH disruption. Method Viral constructs AAV2/8.EF1a.mCherry.flex.DTA (AAV-DTA), or control virus AAV2/8.EF1a.flex.mCherry were injected bilaterally in the VH of postnatal day 14 CaMKII and PV-Cre mice to ablate excitatory and PV cells respectively. Schizophrenia-relevant behaviors – amphetamine- induced locomotor activity, social interaction and spatial learning and memory - were assessed in male and female mice at ~P70. Whole-cell recordings were made in the mPFC to assess cellular activity. Immunohistochemistry and microglia inhibitors were used to assess PFC microglial phenotypes. Results Our ablation procedure resulted in a progressive loss (50-60%) of CaMKII and PV-expressing neurons in the vCA1 of AAV-DTA groups. PV cell depletion resulted in increased cFos-labeled cells, whereas CaMKII depletions led to a decreased cFos in the vCA1, indicating hyper- and hypoexcitability of VH after PV and CaMKII ablations, respectively. In the behavioral studies, no significant differences in spontaneous locomotor activity were observed between the groups. However, adolescent CaMKII-neuron ablation led to an attenuation of d-amphetamine -induced locomotor activity, whereas depletions of PV- neurons caused an enhanced activity. In cognitive tests, CaMKII, but not PV cell-ablation, led to a significant impairment in spatial working memory in matching-to-place task and decreased spontaneous alternation in the Y-maze. Both CaMKII and PV cell-ablated groups showed similar deficits in social novelty memory. Electrophysiological recordings revealed that juvenile VH CaMKII ablations led to impaired mPFC pyramidal cell firing output and a persistent increase in excitatory and decrease in inhibitory synaptic inputs onto pyramidal cells at adulthood. Juvenile CaMKII ablation also resulted in altered density and morphology of mPFC microglia consistent with a phagocytic state. Systemic administration of a microglia depleting drug PLX 3397 significantly rescued Y-maze deficit in VH CaMKII ablated mice. Discussion & Conclusion Our data suggest that adult behavioral vulnerabilities to juvenile VH disruptions are cell-type dependent. VH excitatory/inhibitory deficits, interacting with periadolescent maturational processes such as PFC microglial activity, may play complementary roles in determining schizophrenia- related phenotypes.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».