Project

Cannabis is the most common illicit drug worldwide, especially among pregnant women. Increasing clinical data indicates the spectrum of behavioral/neurobiological alterations associated with prenatal cannabis exposure (PCE), proving its long-term negative impact on next generation health. Children exposed in utero to delta9-tetrahydrocannabinol (THC), the main of cannabis’ psychoactive ingredient, show its detrimental impact on cognitive development, including a proneness to psychotic-like
episodes (PLE). To identify molecular mechanisms and preventative/therapeutic strategies for these negative effects before adolescence is needed to confer resilience towards mental conditions falling under psychotic spectrum. Our data, obtained in a rat model of PCE, point to sex-specific unambiguous enduring molecular and cellular adaptations of brain dopamine (DA) and kynurenic acid (KYNA) signaling resulting in maladaptive network function and its behavioral readouts, including deficits of sensorimotor gating function. This latter can be measured across species by means of the pre-pulse inhibition (PPI) of the startle reflex and startle habituation (SH). Within a very complex circuit, DA and KYNA serve as endogenous modulators of PPI/SH. Disinhibition of DA cells of the ventral tegmental area (VTA) and elevated KYNA levels underpin PPI/SH deficits, thereby contributing to pathophysiology of psychoses. We propose to characterize PCE effects on DA and KYNA signaling by a) capturing an at-risk phenotype for PLE by focusing on KYNA signaling in VTA cellular and molecular mechanisms presumably driving this outcome; b) assessing preventative therapeutic potential of interfering with KYNA actions at prepuberty. We will test our hypothesis in following two specific independent and interconnected aims. Aim 1: Are elevated KYNA levels involved in PCE-induced derangement of DA developmental trajectory at preadolescence? Electrophysiological, behavioral and neurochemical testing will be combined by capitalizing on both our PCE rat model and a transgenic mouse model of spontaneously increased
KYNA levels (i.e., Kmo-/- mice), and the results will be compared with our previous data. We will also implement a clinical setting to examine whether mothers of pediatric patients investigated for suspected neurodevelopmental disorders used cannabis preparations during pregnancy, and will correlate peripheral markers (e.g., saliva KYNA levels) with child behavioral and cognitive profiles. Aim 2: Can we rescue PCE-induced vulnerable offspring by interfering with KYNA actions at prepuberty? We will determine whether pharmacological interventions blocking KYNA effects would prevent maladaptive neurochemical, synaptic and behavioral phenotypic features of PCE progeny. Since many of the enzymes involved in KYNA signaling are “druggable”, these results cou