469. EFFECT OF DEVELOPMENTAL DEFICITS IN VENTRAL HIPPOCAMPAL EXCITATORY AND INHIBITORY NEURONS IN SCHIZOPHRENIA-RELEVANT PHENOTYPES IN MICE
Notice bibliographique
Résumé
Abstract Background Structural and functional abnormalities in the anterior hippocampus, presumably of developmental origin, are consistently reported in individuals with schizophrenia. Rodent studies have shown that the ventral hippocampus (VH; analogous to the anterior hippocampus in humans and primates) strongly influences cognitive, social and emotional behaviors of relevance to schizophrenia. Based on the hippocampal excitatory and inhibitory neuronal deficits in schizophrenia, we hypothesized that juvenile/early adolescence ablation of excitatory/inhibitory neurons in the mice VH may result in adult behavioral/cellular abnormalities described in schizophrenia. Aims & Objectives We investigated the behavioral and neural consequences of juvenile ablation of VH excitatory (glutamatergic) or inhibitory (parvalbumin, PV) neurons in male and female mice. Behaviors were studied at young adult ages after diphtheria toxin A (DTA)-induced ablation of VH 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. Amphetamine-induced locomotor activity, social interaction, anxiety like behavior and spatial learning and memory were assessed in male and female mice at young adulthood. Whole-cell recordings were made in the mPFC to assess cellular activity. Immunohistochemistry and microglia inhibitors were used to assess PFC microglial involvement in behavioral changes. 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 the 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. CaMKII cell-ablation led to significant impairments in spatial and reversal learning in Morris water maze and decreased spontaneous alternation in the Y-maze, whereas PV cell ablation showed impairments only in reversal learning and memory. Both CaMKII and PV cell-ablated groups showed deficits in social novelty memory. CaMKII depletion had no significant effect; however, PV ablated animals showed significantly decreased anxiety-like behavior in the elevated plus maze. No significant effect of sex was detected in any behaviors. Electrophysiological recordings revealed that 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. 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 CaMKII ablated mice. Discussion & Conclusions 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 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».