# Perinatal cannabinoids delay KCC2 expression and lead to neurodevelopmental abnormalities

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2020 · $309,754

## Abstract

Cannabis is the most frequently used illicit drug. Maternal perinatal cannabis use has been associated with a
range of adverse neurodevelopmental consequences in the offspring. The underlying mechanism(s) remain
incompletely understood, but are consistent with impaired cortical neuronal circuit formation. A coordinated
program of transcriptional and physiological events governs the assembly of cortical circuits. The evolutionary
conserved switch of gamma amino butyric acid (GABA) from an excitatory to an inhibitory neurotransmitter is
crucial to the normal development of cortical circuits and associated behaviors. The switch is primarily driven
by increased expression of a potassium/chloride co-transporter, KCC2, which extrudes chloride from the cell.
In our preliminary experiments, we have found that administration of a synthetic cannabinoid or THC for the
first 10 days after birth to lactating rat and mice dams suppresses KCC2 expression in the PFC at postnatal
days 10-15, prolonging the time during which GABA excites PFC networks. Perinatal exposure also impaired
prefrontal cortex synaptic plasticity and cognitive or social behaviors in the adult progeny of both sexes.
The proposed work will follow up these exciting preliminary data to determine the immediate and long-lasting
effects of the cannabinoid-induced delay in KCC2 expression by addressing three specific aims.
Aim 1. Identify the early molecular, functional and behavioral consequences of exposing dams to THC
± CBD during lactation on the progeny of both sexes. These experiments will characterize the early
consequences on neuronal circuits in the PFC, determine THC's mechanism (and possible antagonism by
cannabidiol (CBD)) to delay KCC2 expression, examine the localization and levels of components of the PFC
endocannabinoid system and measure ecologically-relevant pup behaviors (ultrasonic vocalizations and
homing following maternal separation) after maternal exposure to cannabinoids.
Aim 2. Determine the long-term consequences of THC ± CBD exposure during lactation. These
experiments will determine if THC ± CBD exposure during lactation has enduring effects on synaptic plasticity
in adolescent and adult, on levels or localization of PFC endocannabinoid components, on naturalistic social
behaviors, and cognitive function.
Aim 3. Strategies to ameliorate the long-term deleterious consequences of THC exposure during
lactation. These experiments will test the hypothesis that enhancing endocannabinoid signaling (CB1 positive
allosteric modulators or inhibitors of eCB degradation) will rescue the behavioral and physiological deficits that
are a consequence of PCE.
Completion of these experiments will reveal the underpinnings of the impact of perinatal THC exposure on
neuronal functions and behavior and provide new therapeutic strategies to ameliorate associated behavioral
deficits.

## Key facts

- **NIH application ID:** 9955229
- **Project number:** 5R01DA046196-03
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** OLIVIER JJ MANZONI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,754
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955229

## Citation

> US National Institutes of Health, RePORTER application 9955229, Perinatal cannabinoids delay KCC2 expression and lead to neurodevelopmental abnormalities (5R01DA046196-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955229. Licensed CC0.

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