PROJECT SUMMARY
The rise in cannabis use during pregnancy has become of increasing concern due to the direct fetal exposure of
the psychoactive component ¿9-Tetrahydrocannabinol (THC). During the third trimester of gestation, the brain
undergoes a ‘growth spurt’ where cannabinoid type-1 receptors (CB1Rs) increase in density. It has been
suggested that endocannabinoids (eCBs) play a role in both synapse formation and the maintenance of synaptic
plasticity, so understanding the effect of increased cannabis exposure is crucial for explaining the mechanisms
of experience-dependent plasticity during the critical period. Furthermore, chronic THC exposure has been
shown to result in desensitization and internalization of CB1Rs soon after chronic THC exposure. Few
experiments have used animal models to study the effects of THC exposure during brain development and its
long-term effects on CB1R function and expression.
Preliminary data from the Medina lab suggests that prenatal THC exposure during the third trimester equivalent
of human gestation in ferrets increases the density of CB1Rs in neurons in the primary visual cortex and leads
to a larger shift in ocular dominance plasticity (ODP), contrary to prenatal alcohol exposure. Thus, we
hypothesize that prenatal exposure to THC during the equivalent of the third trimester of human gestation leads
to a reduction in expression and function of CB1Rs during the first days after exposure followed by a “rebound”
where expression and function of these receptors increases. These changes in CB1R expression and function
will initially reduce (at P34) and posteriorly increase (at P48) ODP. To test this hypothesis, in Aim 1.1 we will use
RNAscope in THC-exposed and control ferrets to determine if there is a decrease in CB1R expression in neurons
in V1 at P34. In Aim 1.2 we will use whole cell patch clamp electrophysiology in these groups to determine a
change in the number of functional CB1Rs, specifically measuring inhibitory and excitatory post synaptic currents
(IPSCs and EPSCs) at P34. We will use in vivo electrophysiology in Aim 1.3 to determine impairment in ODP at
P34. We will again use RNAscope in Aim 2.1 to determine if there is an increase in CB1R expression at P48 in
THC-treated ferret V1. In Aim 2.2 we will use whole cell patch clamp electrophysiology to determine if chronic
THC exposure leads to an increase in functional CB1Rs, specifically measuring IPSCs and EPSCs. Finally, we
will use in vivo electrophysiology in Aim 2.3 to determine if chronic THC exposure facilitates ODP and results in
a larger shift in ocular dominance at P48, as shown in our preliminary data.
We are confident in our approach based on previous literature, preliminary data, and our success in establishing
a novel prenatal THC exposure model in ferrets. This proposal utilizes this novel animal model to investigate a
problem of growing national concern using multiple technical approaches and will allow for the growth of the PI
Ms. Pruitt as an independent researcher.
