JUVENILE ABLATION OF EXCITATORY AND INHIBITORY NEURONS IN THE VENTRAL HIPPOCAMPUS OF MICE LEAD TO DISSOCIABLE SCHIZOPHRENIA- RELEVANT PHENOTYPES AT YOUNG ADULTHOOD
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".