Endocannabinoid signals in the developmental programming of delayed-onset neuropsychiatric and metabolic illnesses

Abstract

It is increasingly recognized that maternal exposure to metabolic (nutritional) stimuli, infections, illicit or prescription drugs and environmental stressors during pregnancy can predispose affected offspring to developing devastating postnatal illnesses. If detrimental maternal stimuli coincide with critical periods of tissue production and organogenesis then they can permanently derail key cellular differentiation programs. Maternal programming can thus either provoke developmental failure directly ('direct hit') or introduce latent developmental errors that enable otherwise sub-threshold secondary stressors to manifest as disease ('double hit') postnatally. Accumulating evidence suggests that nervous system development is tightly controlled by maternal metabolic stimuli, and whose synaptic wiring and integrative capacity are adversely affected by dietary and hormonal challenges, infections or episodes of illicit drug use. Endocannabinoids, a family of signal lipids derived from polyunsaturated fatty acids, have been implicated in neuronal fate determination, the control of axonal growth, synaptogenesis and synaptic neurotransmission. Therefore the continuum and interdependence of endocannabinoid actions during the formation and function of synapses together with dynamic changes in focal and circulating endocannabinoid levels upon maternal nutritional imbalance suggest that endocannabinoids can execute the 'reprogramming' of specific neuronal networks. In the present paper, we review molecular evidence suggesting that maternal nutrition and metabolism during pregnancy can affect the formation and function of the hippocampus and hypothalamus by altering endocannabinoid signalling such that neuropsychiatric diseases and obesity respectively ensue in affected offspring. Moreover, we propose that the placenta, fetal adipose and nervous tissues interact via endocannabinoid signals. Thus endocannabinoids are hypothesized to act as a molecular substrate of maternal programming.

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

“…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). Supporting this hypothesis, we have recently analyzed the expression of cannabinoid CB1 and CB2 receptors mRNA in the hypothalamus of adult offspring born from mothers exposed to pre- and gestational moderate caloric restriction and we have found a clear upregulation in the expression of both receptors, indicating long-term alterations in the offspring as result of maternal undernutrition (Ramírez-López submitted).…”

“…Calorie-restricted rat dams tended to weigh less than controls at birth and their endocannabinoid levels might not have been restored to normal. Thus, the endocannabinoid levels in new born rats might reflect the maternal status, due to the fact that long fatty acids can be transferred through the placenta and the fetus are not fully able to modify fatty acid structures (Keimpema et al, 2013). Future research will address these possibilities.…”

“…Moreover, the arachidonic acid is a derivative of the linoleic acid, an essential dietary n-6 fatty acid (Hansen and Artmann, 2008). Therefore, an inadequate maternal diet might alter the endocannabinoid signaling and disturb the establishment of circuitries regulating metabolism, learning and emotional control, leading to metabolic and neurobehavioral abnormalities later in life (Keimpema et al, 2013; Ramírez-López et al, 2016). However, further investigation is necessary to clarify the role of the endocannabinoid system in these processes.…”

At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring

“…CNS vulnerability is a leading fingerprint of harmful developmental drug effects, and predominantly manifest as functional impairments in early childhood or adolescence, much less so by birth (13). These observations fuel the "double-hit" hypothesis that defines sub-threshold stimuli as triggers of severe malfunction of sensitized yet nonsymptomatic neuronal circuits with often considerable delay in postnatal life (14,15). Nevertheless, cannabis-induced early prenatal lethality could be underestimated.…”

“…Nevertheless, cannabis-induced early prenatal lethality could be underestimated. Rodent and chick experiments show that marijuana embryotoxicity manifests as neural plate aplasia at early intrauterine time points which, when considering their human equivalents (gestational days [15][16][17][18][19], would likely be clinically misinterpreted as a lack of embryo implantation (16).…”