Perinatal cannabinoids delay KCC2 expression and lead to neurodevelopmental abnormalities

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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.