Abstract summary: “Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), (Pasman and colleagues) identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2 (cell adhesion molecule 2), which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use.” The authors concluded that the study gives new insights into the etiology of cannabis use and its relation with mental health.
Pasman JA, Verweij KJH, Gerring Z, Stringer S, Sanchez-Roige S, Treur JL, Abdellaoui A, Nivard MG, Baselmans BML, Ong JS, Ip HF, van der Zee MD, Bartels M et al: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nature Neurosci. [Epub ahead of print, August 27, 2018; doi: 10.1038/s41593-018-0206-1].
Abstract: “The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.”
Nasca C, Bigio B, Lee FS, Young SP, Kautz MM, Albright A, Beasley J, Millington DS, Mathé AA, Kocsis JH, Murrough JW, McEwen BS and Rasgon N: Acetyl-1-carnitine deficiency in patients with major depressive disorder. Proc. Natl. Acad. Sci. USA [Epub ahead of print, July 30, 2018; pii: 201801609. doi: 10.1073/pnas.1801609115 ].
Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. In this study, the authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation patterns, and whether clinical characteristics of major depression have a further impact on these patterns.
Compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score.
Han LKM, Aghajani M, Clark SL, Chan RF, Hattab MW, Shabalin AA, Zhao M, Kumar G, Xie LY, Jansen R, Milaneschi Y, Dean B, Aberg KA, van den Oord EJCG, and Penninx BWJH: Epigenetic Aging in Major Depressive Disorder. Amer. J. Psychiatry 175:774–782 (2018).
“Transgenerational epigenetic inheritance refers to the transmission of epigenetic information through the germline. While it has been observed in plants, nematodes and fruit flies, its occurrence in mammals-and humans in particular-is the matter of controversial debate, mostly because the study of transgenerational epigenetic inheritance is confounded by genetic, ecological and cultural inheritance.” In this paper, Horsthemke discusses the phenomenon of transgenerational epigenetic inheritance and the difficulties in experimental and observational studies.
Horsthemke B: A critical view on transgenerational epigenetic inheritance in humans. Nature Commun. 9(1): 2973 (2018); doi: 10.1038/s41467-018-05445-5.
“Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide.” Here Patel and colleagues report that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed analyses revealed that aspirin, but not other structural homologs, acts as a PPARα ligand through direct binding at the Tyr314 residue of the PPARα ligand-binding domain. On binding to PPARα, aspirin stimulated hippocampal plasticity via transcriptional activation of cAMP response element-binding protein (CREB). Low-dose aspirin also improved hippocampal function in an animal model of Alzheimer’s disease via PPARα. These results delineate a new receptor of aspirin through which it may protect memory and learning.
Patel D, Roy A, Kundu M, Jana M, Luan C-H, Gonzalez FJ, and Pahan K: Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory. Proc. Natl. Acad. Sci. USA 115 (31): E7408-E7417 (2018).
“Recent research has identified human subjects who have highly superior autobiographical memory (HSAM). Here, (Santangelo and colleagues) investigated, using fMRI, the neural activation induced by retrieval of autobiographical memories (AMs) and semantic memories (SMs) in subjects with HSAM and control subjects. While their brains were being scanned, subjects had to retrieve autobiographical memories as well as semantic memories (e.g., examples of animals). The subjects with HSAM displayed a superior ability to retrieve details of autobiographical memories, supported by enhanced activation of several brain regions, including the medial prefrontal cortex and temporoparietal junction, as well as increased connectivity of the prefrontal cortex with the hippocampus, a region well known to be involved in memory representation.” The authors suggest that activation of these systems may play a critical role in enabling HSAM.
Santangelo V, Cavallina C, Colucci P, Santori A, Macrì S, McGaugh JL, and Campolongo P: Enhanced brain activity associated with memory access in highly superior autobiographical memory. Proc. Natl. Acad. Sci. USA 115(30):7795-7800 (2018).
Abstract: “Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.”
- “Episodic memory has limited utility as a diagnostic and outcome measure for preclinical Alzheimer disease (AD).
- Spatial navigation deficits have the potential to detect underlying pathophysiology in preclinical AD.
- The brain areas affected earliest by AD pathophysiology are key nodes in the spatial navigation network.
- Genetically at-risk individuals show altered spatial navigation patterns before any episodic memory symptom onset.”
- Spatial navigation is emerging as a potential cost-effective cognitive biomarker to detect AD in the preclinical stages, which has important implications for future diagnostics and treatment approaches.
- Future spatial navigation benchmarks and standardization of spatial navigation tests are needed to realize this goal.”
Coughlan G, Laczó J, Hort J, Minihane A-M, Hornberger M: Spatial navigation deficits – overlooked cognitive marker for preclinical Alzheimer disease? Nature Reviews Neurol. 14: 496-506 (2018).
Hippocampus-dependent, event-related memories formed in early infancy in human and non-human animals are rapidly forgotten. Recently the authors reported that high levels of hippocampal neurogenesis contribute to accelerated rates of forgetting during infancy. Here, they ask whether these memories formed in infancy are permanently erased (i.e., storage failure) or become progressively inaccessible with time (i.e., retrieval failure). To do this, they developed an optogenetic strategy that permanently expressed channelrhodopsin-2 (ChR2) in neuronal ensembles that were activated during contextual fear encoding in infant mice. They then examined whether reactivation of ChR2-tagged ensembles in the dentate gyrus was sufficient for memory recovery in adulthood. They found that optogenetic stimulation of tagged dentate gyrus neurons recovered “lost” infant memories up to 3 months following training and that memory recovery was associated with broader reactivation of tagged hippocampal and cortical neuronal ensembles. Thus, infant memories may be recovered under specific conditions and are not permanently lost.
Guskjolen A, Kenney JW, de la Parra J, Yeung BA, Josselyn SA, Frankland PW: Recovery of “Lost” Infant Memories in Mice. Curr. Biol.pii: S0960-9822(18)30695-X. doi: 10.1016/j.cub.2018.05.059. [Epub ahead of print, June 26, 2018].
Abstract: “The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.”
Brusini I, Carneiro M, Wang C, Rubin C-J, Ring H, Afonso S, José A et al: Changes in brain architecture are consistent with altered fear processing in domestic rabbits. Proc.Natl.Acad. Sci. USA 115 (28): 7380-7385 (2018).
“While accounting for only 2% of the body’s weight, the brain utilizes up to 20% of the body’s total energy. Not surprisingly, metabolic dysfunction and energy supply-and-demand mismatch have been implicated in a variety of neurological and psychiatric disorders. Mitochondria are responsible for providing the brain with most of its energetic demands, and the brain uses glucose as its exclusive energy source. Exploring the role of mitochondrial dysfunction in the etiology of psychiatric disease is a promising avenue to investigate further. Genetic analysis of mitochondrial activity is a cornerstone in understanding disease pathogenesis related to metabolic dysfunction. In concert with neuroimaging and pathological study, genetics provides an important bridge between biochemical findings and clinical correlates in psychiatric disease. Mitochondrial genetics has several unique aspects to its analysis, and corresponding special considerations.” Here, the authors review the components of mitochondrial genetic analysis – nuclear DNA, mitochondrial DNA, mitochondrial pathways, pseudogenes, nuclear-mitochondrial mismatch, and microRNAs – that could contribute to an observable clinical phenotype. This paper highlights psychiatric diseases that can arise due to dysfunction in these processes, with a focus on schizophrenia and bipolar disorder.
Cuperfain A.B., Zhang Z.L., Kennedy J.L., Gonçalves V.F.: The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease. Mol. Neuropsychiatry 4(1): 52-69 (2018).