Impaired hippocampal-dependent memory and reduced parvalbumin-positive interneurons in a ketamine mouse model of schizophrenia
Open accessAbstract
The hippocampus of patients with schizophrenia displays aberrant excess neuronal activity which affects cognitive function. Animal models of the illness have recapitulated the overactivity in the hippocampus, with a corresponding regionally localized reduction of inhibitory interneurons, consistent with that observed in patients. To better understand whether cognitive function is similarly affected in these models of hippocampal overactivity, we tested a ketamine mouse model of schizophrenia for cognitive performance in hippocampal- and medial prefrontal cortex (mPFC)-dependent tasks. We found that adult mice exposed to ketamine during adolescence were impaired on a trace fear conditioning protocol that relies on the integrity of the hippocampus. Conversely, the performance of the mice was normal on a delayed response task that is sensitive to mPFC damage. We confirmed that ketamine-exposed mice had reduced parvalbumin-positive interneurons in the hippocampus, specifically in the CA1, but not in the mPFC in keeping with the behavioral findings. These results strengthened the utility of the ketamine model for preclinical investigations of hippocampal overactivity in schizophrenia.
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Chronic high-dose ketamine treatment is used as a model for schizophrenia-like behavior in animal models and reduces PV interneuron function in this model.
“As chronic high-dose ketamine treatment is used as a model for schizophrenia-like behavior in animal models and reduces PV interneuron function in this model (Frohlich and Van Horn, 2014;Jeevakumar et al., 2015;Koh et al., 2016), it was hypothesized that a single low-dose ketamine treatment might reduce PV interneuron activity therapeutically to promote cortical disinhibition and ODP.”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Koh et al., 2016
The Methods (§2.2) describe repeated ketamine treatment (16 mg/kg, three times weekly for a month), and the Introduction (§1) identifies the regimen as a schizophrenia mouse model. The Results (§3.4) show fewer parvalbumin-positive interneurons in hippocampal CA1, but not in the other regions tested. The paper does not classify this dose as “high” or directly measure PV interneuron function; the Discussion (§4) infers reduced inhibitory control from the cell counts. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAnimal models that mimic schizophrenia reproduce the loss of PV-INs in the hippocampus.
“Animal models that mimic schizophrenia replicate the loss of PV-INs in the hippocampus [6,14,15], and show a loss of PV fluorescence per cell in prelimbic regions [16].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [14]
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- McEchron MD Bouwmeester H Tseng W Weiss C Disterhoft JF Hippocampectomy disrupts auditory trace fear conditioning and contextual fear conditioning in the rat Hippocampus 1998 8 6 638 646 9882021
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Parvalbumin interneuron vulnerability and brain disorders
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Psychedelics and Neural Plasticity: Therapeutic Implications
Grieco, S. F., Castrén, E., Knudsen, G. M., Kwan, A. C., Olson, D. E., Zuo, Y., Holmes, T. C., & Xu, X. (2022) · The Journal of Neuroscience · doi:10.1523/jneurosci.1121-22.2022 · Cited by 82 · see citing works
“…behavior in animal models and reduces PV interneuron function in this model (Frohlich and Van Horn, 2014; Jeevakumar et al., 2015; Koh et al., 2016), it was hypothesized that a single low-dose ketamine treatment might reduce PV inter-neuron activity therapeutically to promote…”
- Authors
- Koh, M. T., Shao, Y., Sherwood, A., & Smith, D. R.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Koh, Ming Teng
- ORCID
- Sherwood, Andrew
- Venue
- Schizophrenia Research
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 171
- Issue
- 1-3
- Pages
- 187-194
- ISSN
- 0920-9964 (ISSN-L)
- PMC
- PMC4762714
- OpenAlex
- W2285024066
- Cited by
- 51
- References
- 68
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 10 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 1
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Schizophrenia Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Silvo O. Conte Center (P50MH094268)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia
- MeSH terms
- Amphetamine, Animals, Conditioning, Classical, Disease Models, Animal, Fear, Hippocampus, Interneurons, Ketamine, Locomotion, Male, Memory Disorders, Mice, Inbred C57BL, Parvalbumins, Reaction Time, Schizophrenia, Time Factors, Mice
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