# Impact of Cannabinoid Across the Lifespan (ICAL)

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $453,944

## Abstract

ICAL SYNAPTIC PROJECT (PROJECT 2): SUMMARY
Disturbances in memory associated with cannabis use during adolescence (1-4) strongly suggest that the drug
has age- and sex-specific effects on synaptic plasticity and associated cognitive functions. There is, however,
little information on the neurobiological bases underlying such effects. Our Project has shown that
adolescent THC exposure (‘ado-THC’) causes pronounced, sexually dimorphic, and enduring
impairments to synaptic plasticity underlying learning. Specifically, we found ado-THC leads to marked
deficits in long-term potentiation (LTP) in the lateral perforant path (LPP) projections to the dentate
gyrus (LPP-LTP) in rodents of both sexes. It also causes enduring deficits in LTP in the CA3 projection
to CA1 (CA1-LTP) but for females only. Importantly, these effects are accompanied by disturbances in
a fundamental aspect of episodic memory known to depend on the LPP. Motivated by evidence that
microglial functions are impaired by ado-THC (Project 1) we tested if these cells normally influence LTP in
hippocampus and found that pharmacological elimination of microglia mimicked the effects of ado-THC on LPP
plasticity and episodic memory but did not impair CA1-LTP. These findings led to a ‘microglia hypothesis’ for
the origin of LPP-LTP and memory problems resulting from ado-THC. The proposed research will test this
hypothesis and evaluate the basis of sex differences in CA1 in three specific aims. Aim 1 will test predictions of
the microglia hypothesis for impairments in LPP plasticity by determining (a) if microglial depletion mimics
effects of ado-THC on synaptic signaling, (b) if newly devised conditional knockout (cKO) mice engineered to
prevent the microglial responses to ado-THC protect LPP-LTP from impairment and (c) if microglial
replacement in adulthood can restore full LPP function after ado-THC. Aim 2 will address the question of why
ado-THC impairs CA1-LTP in females only. It is known that female, but not male, rodents require local
estrogen acting at synaptic estrogen receptors to induce stable CA1-LTP. Preliminary results indicate that ado-
THC blocks estrogen effects on synaptic strength and spine F-actin content in CA1. Aim 2 will test the
hypothesis that ado-THC disrupts estrogen responsivity at excitatory synapses and specifically impairs
estrogen effects on the actin cytoskeleton that stabilize female CA1-LTP. Finally, Aim 3 will determine the
breadth of ado-THC effects on episodic memory and if these changes are (a) sexually dimorphic and (b)
depend on microglial dysfunction. Together, the studies will identify synaptic mechanisms through which ado-
THC exerts sexually dimorphic effects on episodic memory and, thus, higher cognitive function.

## Key facts

- **NIH application ID:** 10932781
- **Project number:** 2P50DA044118-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Christine M Gall
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,944
- **Award type:** 2
- **Project period:** 2018-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932781

## Citation

> US National Institutes of Health, RePORTER application 10932781, Impact of Cannabinoid Across the Lifespan (ICAL) (2P50DA044118-05A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932781. Licensed CC0.

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