Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Abstract

Energy-dense, yet nutritionally poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acids (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFA deficiency lasting from adolescence into adulthood. Starting nutritional deficits in dietary n-3 PUFAs during adolescence decreased n-3 PUFAs in both medial prefrontal cortex (mPFC) and nucleus accumbens, increased anxiety-like behavior, and decreased cognitive function in adulthood. Importantly, we discovered that endocannabinoid/mGlu 5 -mediated LTD in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent LTP was also lacking in the n-3-deficient group. Pharmacological enhancement of the mGlu 5 /eCB signaling complex, by positive allosteric modulation of mGlu 5 or inhibition of endocannabinoid 2-arachidonylglycerol degradation, fully restored synaptic plasticity and normalized emotional and cognitive behaviors in malnourished adult mice. Our data support a model where nutrition is a key environmental factor influencing the working synaptic range into adulthood, long after the end of the perinatal period. These findings have important implications for the identification of nutritional risk factors for disease and design of new treatments for the behavioral deficits associated with nutritional n-3 PUFA deficiency.

Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood

“…First, eCBmediated LTD was entirely absent at deep layer PFC synapses in slices obtained from the progeny of THC-treated dams. This finding is in line with previous findings from our lab demonstrating a loss of eCB-LTD in the PFC of in utero exposed offspring at adulthood 26 and extends upon previous findings that defects in PFC plasticity correlate with social dysfunction in other contexts, such as a mouse model of dietary polyunsaturated fat imbalance 33 . Further, the loss of eCB-LTD correlated with an enhanced magnitude of mGlu2/3-LTD in the THC-exposed progeny.…”

“…Whole cell patch-clamp recordings were performed with an Axopatch-200B amplifier as previously described 26,[31][32][33] . Data were low pass filtered at 2kHz, digitized (10 kHz, DigiData 1440A, Axon Instrument), collected using Clampex 10.2 and analyzed using Clampfit 10.2 (all from Molecular Device, Sunnyvale, USA).…”

Sex‐specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212‐2 depend on mGlu5 receptor signalling

“…correlates with increases in the levels of protein expression of mGlu 5 R (Liang et al, 2014). Based on this evidence and our recent findings on the interaction between cannabinoids and mGlu 5 R in modulating behavioural and synaptic states in the context of nutrition (Manduca et al, 2017) and social interaction in male offspring after in utero cannabinoid exposure (Bara et al, 2018), we here investigated whether…”

“…Indeed, the developmentally dependent increase in endocannabinoid mobilization (that occurs between the neonatal and juvenile stages) correlates with increases in the levels of protein expression of mGlu 5 R (Liang et al, ). Based on this evidence and our recent findings on the interaction between cannabinoids and mGlu 5 R in modulating behavioural and synaptic states in the context of nutrition (Manduca et al, ) and social interaction in male offspring after in utero cannabinoid exposure (Bara et al, ), we here investigated whether the positive allosteric modulator of mGlu 5 R CDPPB normalized the behavioural deficits induced by in utero cannabinoid exposure.…”

“…Animals were habituated to the experimental arena (40 × 40 cm) without objects for 10 min daily for 2 days before testing. This task consisted of two sample phases and one test trial (Barker, Bird, Alexander, & Warburton, 2007;Manduca et al, 2017). In each sample phase, rats were allowed to explore two copies of an identical object for a total of 4 min.…”