# Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $760,343

## Abstract

Schizophrenia is a debilitating psychiatric disorder that effects 1% of the population, with an additional 2-3%
developing a schizoaffective disorder. SCZ patients exhibit a spectrum of cognitive deficits including defective
episodic memory, present prior to the onset of psychosis and frequently expressed in relatives of affected
individuals. Episodic memory formation is dictated in part by spatially tuned (place cell) activity of principal
cells in the hippocampus. The biological mechanisms driving this learning capacity in the healthy hippocampus
remain largely unknown, let alone their disruption in schizophrenia, leaving large gaps in our knowledge that
need to be addressed. Using in vivo functional imaging in mouse dorsal hippocampal area CA1 during head-fixed
during learning behaviors, we recently uncovered specific alterations in in vivo physiological properties of CA1
pyramidal cells in the Df(16)A+/− transgenic mouse model of 22q11.2 deletion syndrome, the largest known
genetic risk to develop SCZ. Df(16)A+/− CA1 place cells exhibit reduced long-term stability, impaired context-
related and lack of reward-related reorganization. A novel form of synaptic plasticity, termed behavioral time-
scale synaptic plasticity (BTSP), has been found to drive rapid formation of spatially selective firing fields in CA1
pyramidal cells; notably, our preliminary studies suggest that this form of plasticity is dysregulated in Df(16)A+/−
mice. We thus hypothesize that BTSP, a major form of plasticity that drives place cell-recruitment during
learning, is disrupted by SCZ risk mutations. These findings at the neuronal population level provide entry points
for dissecting the underlying cellular, molecular and microcircuit dysfunctions caused by schizophrenia risk
mutations. To gain these mechanistic insights we will unite the complementary expertise of the Losonczy lab and
the Gogos lab in etiologically valid genetic mouse models of neuropsychiatric disorders to carry out multiscale
dissection of microcircuit, cellular and molecular pathophysiology of schizophrenia-related memory deficits in
the adult mouse hippocampal CA1 circuitry. Aim 1 is aimed at assessing altered synaptic plasticity in CA1
pyramidal cells during episodic learning in Df(16)A+/− mice. Aim 2 deals with dissecting inhibitory microcircuit
dynamics during episodic learning, while Aim 3 is focused at dissecting altered excitatory and neuromodulatory
input dynamics to CA1 during episodic learning in Df(16)A+/− mice. Taken together, Aims 1-3 provide a tractable
path to a deeper, mechanistic understanding of hippocampus-related cognitive memory deficits in
schizophrenia.

## Key facts

- **NIH application ID:** 10241386
- **Project number:** 5R01MH124047-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** JOSEPH A GOGOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $760,343
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241386

## Citation

> US National Institutes of Health, RePORTER application 10241386, Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion (5R01MH124047-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241386. Licensed CC0.

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