Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB ₁ receptors on developing cortical neurons

Abstract

The CB 1 cannabinoid receptor, the main target of Δ 9 -tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB 1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB 1 receptor genetic ablation, and CB 1 -null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB 1 expression-rescue strategy in a CB 1 -null background. Early and selective CB 1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB 1 -null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB 1 -dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB 1 signaling.R ecreational cannabis consumption during pregnancy can exert deleterious consequences in the progeny, including anxiety, depression, psychosis risk, and cognitive and social impairments (1, 2). In the last two decades, important advances in our understanding of the endocannabinoid system have paved the way to elucidate the particular neurobiological substrates responsible for some cannabinoid-induced neurological alterations in adult animals and humans (3). The currently accepted scenario is that the CB 1 cannabinoid receptor (CB 1 R), the main target of marijuana-derived cannabinoids, is located presynaptically and, upon engagement by endocannabinoids [2-arachidonoylglycerol (2-AG) and anandamide], can act as a key neuromodulatory and plasticity-tuning signaling platform at many different mature synapses (4). In fact, CB 1 R constitutes one of the most abundant and functionally relevant G proteincoupled receptors in several regions of the adult mammalian brain (3, 4).Manipulation of CB 1 R function in animal models, either directly or indirectly, by modulating 2-AG or anandamide levels through the main endocannabinoid-synthesi...

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

“…Notably, Δ 9 -THC (3 mg/kg, i.p.) administered to a pregnant female mouse from 5 consecutive days at embryonic days 12.5–16.5 reduced seizure latency and reduced the required PTZ dose to induce seizure in offspring [82], raising the possibility that Δ 9 -THC can cause pro-convulsive effects in future generations. Tetrahydrocannabivarin (Δ 9 -THCV), a structurally related compound to Δ 9 -THCV that acts as a CB 1 R antagonist and CB 2 R partial agonist, reduced seizure incidence when given 0.25 mg/kg i.p., 30 min prior to PTZ-induced seizure in rats.…”

Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring

“…Indeed, during the prenatal and postnatal periods endocannabinoids levels reach a peak in concentration, which correlates with neurodevelopment processes occurring in these specific age stages (Berrendero et al, 1999). Moreover, alterations of endocannabinoid signaling by prenatal administration either of cannabinoid receptor agonists, such as THC (Δ 9 -Tetrahydrocanabinol), or antagonists, is associated to impairment in neuronal activity, cortical connections and emotional behavior (Rodríguez de Fonseca et al, 1991; Antonelli et al, 2005; Bernard et al, 2005; Moreno et al, 2005; de Salas-Quiroga et al, 2015). Importantly, our data suggest that prolonged prepregnancy-gestational undernutrition could have altered the normal fluctuations of endocannabinoid levels and thus, the establishment of functional circuitries involved in metabolism, ultimately leading to metabolic abnormalities later in life, as proposed by Keimpema et al (2013).…”

“…The endocannabinoid system plays a pivotal role in brain development (Maccarrone et al, 2014) and the disruption of endocannabinoid signaling in early stages of development has been associated to disturbances in neuronal activity, deficient cortical connections and behavior alterations (Rodríguez de Fonseca et al, 1991; Antonelli et al, 2005; Bernard et al, 2005; Moreno et al, 2005; de Salas-Quiroga et al, 2015). Moreover, the type of diet can modify the endocannabinoid content in different tissues, including the brain during development (Berger et al, 2001; Matias et al, 2003; Ramírez-López et al, 2016).…”

Cannabis use during pregnancy: Pharmacokinetics and effects on child development

“…A key function of CB 1 R in mature neurons is to modulate the release of neurotransmitters such as glutamate and GABA (Bloomfield et al, 2016; Katona and Freund, 2008, 2012). Central to this review, activation of CB 1 R during neuronal development influences cell proliferation, migration, and differentiation through control of the expression of key factors, including brain-derived nerve factor (Calvigioni et al, 2014; de Salas-Quiroga et al, 2015; Marsicano et al, 2003). CB 1 R are also expressed by cells in the periphery, including in reproductive tissues (Pertwee et al, 2010).…”