| dc.description.abstract | Prenatal cannabinoid exposure (PCE) has increased despite concerns that it may produce lasting effects on brain development and behavior. Delta-9-tetrahydrocannabinol (THC), the primary psychoactive substance of cannabis, crosses the placental barrier and activates cannabinoid receptor type 1 (CB₁R), a key regulator of endocannabinoid signaling during neurodevelopment. Because the endocannabinoid system contributes to the maturation of hippocampal circuits that support learning and memory, PCE may disrupt hippocampal function; however, the underlying mechanisms remain unclear. This dissertation used two prenatal THC exposure models to characterize the developmental, behavioral, molecular, anatomical, and physiological consequences of PCE. In a translational vapor inhalation model, toxicokinetic analyses confirmed systemic THC exposure and neonatal transfer. PCE altered maternal and offspring developmental measures and produced sex-dependent behavioral abnormalities during adolescence, including increased anxiety-like behavior and marginal impairment of recognition memory. These effects were accompanied by sex-dependent changes in hippocampal GABAergic-associated protein expression and CB₁R-associated inhibitory circuitry.
A second study used a subcutaneous THC exposure model to determine whether these molecular and anatomical alterations were associated with persistent changes in hippocampal physiology. Following confirmation of THC formulation stability, developmental outcomes, synaptosomal protein expression, and extracellular field recordings were evaluated. PCE increased vesicular glutamate transporter 1 expression in both sexes and produced sex-specific alterations in proteins associated with inhibitory signaling. PCE did not alter basal excitatory synaptic transmission in the absence of gabazine (GBZ), a competitive gamma-aminobutyric acid type A receptor (GABAAR) antagonist. However, partial GABAAR blockade revealed sex-dependent alterations in presynaptic recruitment and short-term plasticity. PCE also reduced long-term potentiation maintenance in both sexes and enhanced long-term depression in males. GBZ modified synaptic depression but did not attenuate the long-term potentiation deficit in THC-exposed offspring.
Together, these findings demonstrate that PCE produces persistent, sex-dependent developmental, behavioral, molecular, anatomical, and physiological alterations that extend into adolescence. Across two exposure paradigms, PCE altered hippocampal excitatory and inhibitory signaling, as well as GABAergic regulation of glutamatergic transmission. These findings indicate that PCE-induced hippocampal dysfunction is not explained solely by excessive inhibitory transmission but instead involves disrupted coordination between glutamatergic and GABAergic signaling and impaired synaptic plasticity. | en_US |
