Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

Abstract

Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less known. We found that an epigenetic and energetic agent, acetyl-L-carnitine (LAC, oral administration), rapidly rescued the depressiveand central and systemic metabolic-like phenotype of LAC-deficient Flinders Sensitive Line rats (FSL). After acute stress during LAC treatment, a subset of FSL continued to respond to LAC (rFSL), whereas the other subset did not (nrFSL). RNA sequencing of the ventral dentate gyrus, a mood-regulatory region, identified metabolic factors as key markers predisposing to depression (insulin receptors Insr, glucose transporters Glut-4 and Glut-12, and the regulator of appetite Cartpt) and to LAC responsiveness (leptin receptors Lepr, metabotropic glutamate receptors-2 mGlu2, neuropeptide-Y NPY, and mineralocorticoid receptors MR). Furthermore, we found that stress-induced treatment resistance in nrFSL shows a new gene profile, including the metabolic regulator factors elongation of long chain fatty acids 7 (Elovl7) and cytochrome B5 reductase 2 (Cyb5r2) and the synaptic regulator NPAS4. Finally, while improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrected a systemic hyperinsulinemia and hyperglicemia in rFSL and failed to do that in nrFSL. These findings establish CNS energy regulation as a factor to be considered for the development of better therapeutics. Agents such as LAC that regulate metabolic factors and reduce glutamate overflow could rapidly ameliorate depression and could also be considered for treatment of insulin resistance in depressed subjects. The approach here serves as a model for identifying markers and underlying mechanisms of predisposition to diseases and treatment responsiveness that may be useful in translation to human behavior and psychopathology. metabolic factors | acetylcarnitine | dentate gyrus | insulin | RNAseq P revious research has shown that agents that influence energy homeostasis, such as the epigenetic molecule acetyl-L-carnitine (LAC), exert rapid antidepressant-like effects by correcting imbalance of the glutamate system in the hippocampus of a genetic rat model of depression, Flinders Sensitive Line rats (FSL), and in a mouse model of stress-induced depressive-like traits (1-3). LAC, which passes through the blood-brain barrier, is a nutritional supplement and is also synthetized in the brain, liver, and kidney (4). Among its beneficial effects on the brain and the body, LAC regulates mitochondrial metabolism by facilitating transfer of fatty acids from the cytosol to the mitochondrial matrix for subsequent β-oxidation (5), needed for energy metabolism, deficits of which have been associated with a variety of diseases, including psychiatric disorders (6). However, the role of energy regulation in depression and in the responsiveness and/or resistance to antidepressants is less known.Because the ventral dentate gyrus (vDG) has a key role in regulating resilie...

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“…Acute stress increases hippocampal MR expression (Gesing et al 2001, Bigio et al 2016), but also a decrease has been reported for MR hnRNA, whereas the effects appeared to depend on strain and methodology (Herman et al 1999). Exposure to synthetic glucocorticoids also increases hippocampal MR (Reul et al 1987(Reul et al , 1989 as do tricyclic antidepressants (Seckl & Fink 1992), whereas aged, chronically stressed and/or depressed individuals have a suppressed brain MR expression (van Eekelen et al 1995, Klok et al 2011b.…”

“…Thus, the MR can operate as a key regulator in a mechanism underlying resilience to stress. Such a crucial role of the brain MR in human resilience is underscored by variations in MR genotype, which were found to predict stress coping style and protection to depression, and by epigenetic modifications of the MR induced by (early) adversity (see Joëls et al 2012, Bigio et al 2016, de Kloet et al 2016.…”

An energetic view of stress: Focus on mitochondria

“…Moreover, LAC deficiency in animal models is associated with metabolic dysregulation, including insulin resistance, elevated triglycerides and leptin that, like the depressive-like behavior, is rapidly corrected by LAC treatment (Bigio et al, 2016). Connecting this to LAC and its actions, research shows that a ketogenic diet that relies on and activates mitochondrial oxidative metabolism ameliorates insulin resistance and Type 2 diabetes, and also increases LAC levels (Berry-Kravis et al, 2001).…”

Epigenetic mechanisms of major depression: Targeting neuronal plasticity

“…This is the first evidence for metabolic signaling to chromatin in the brain and indicates a critical role for this type of signaling in cognitive function. Molecules that affect energy homeostasis, such as the epigenetic molecule acetyl‐ l ‐carnitine that is produced during normal metabolism, affect and hence provide rapid antidepressant‐like activity . These results suggest that metabolic pathways are linked to epigenetic regulation of genes associated with depression.…”