Pearls and Pitfalls in Experimental Models of Spreading Depression.

Pearls and pitfalls in experimental models of spreading depression.

Cephalalgia. 2013 Jun; 33(8): 604-13
Ayata C

Spreading depression (SD) is the electrophysiological substrate of migraine aura and a potential trigger for headache. Since its discovery by Leão in 1944, SD has transformed from being viewed as an epiphenomenon into a therapeutic target relevant in the pathophysiology of migraine and brain injury.Despite decades of research, the underpinnings of SD are still poorly understood, hampering our efforts to selectively block its initiation and spread. Experimental models have nevertheless been useful to measure the likelihood of SD occurrence (i.e. SD susceptibility) and characterize genetic, physiological and pharmacological modulation of SD in search of potential therapies, such as in migraine prophylaxis and stroke. Here, I review experimental SD susceptibility endpoints and surrogates, and minimum essential model requirements to improve their utility in drug screening.A critical reappraisal of strengths and caveats of experimental models of SD susceptibility is needed to set standards and improve data quality, interpretation and reconciliation. HubMed – depression


Nitric oxide-dependent LTD but not endocannabinoid-LTP is crucial for visual recognition memory.

J Physiol. 2013 May 13;
Tamagnini F, Barker GR, Warburton CE, Burattini C, Aicardi G, Bashir Z

Synaptic plasticity in perirhinal cortex is essential for recognition memory. Nitric oxide (NO) and endocannabinoids (eCBs), which are produced in the postsynaptic cell and act on the presynaptic terminal, are implicated in mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in other brain regions. In this study we examine these two retrograde signalling cascades in perirhinal cortex synaptic plasticity and in visual recognition memory in the rat. We show that inhibition of NO-dependent signalling prevented both carbachol- and activity (5Hz)- dependent LTD but not activity (100 Hz theta burst)-dependent LTP in the rat perirhinal cortex in vitro. In contrast, inhibition of the eCB-dependent signalling prevented LTP but not the two forms of LTD in vitro. Local administration into perirhinal cortex of the NOS inhibitor NPA (2 ?M), disrupted acquisition of long-term visual recognition memory. In contrast, AM251 (10 ?M), a CB1 antagonist, did not impair visual recognition memory. The results of this study demonstrate dissociation between putative retrograde signalling mechanisms in LTD and LTP in perirhinal cortex. Thus LTP relies on cannabinoid but not NO signalling whilst LTD relies on NO- but not eCB-dependent signalling. Critically, these results also establish for the first time that NO-, but not eCB-dependent signalling is important in perirhinal cortex-dependent visual recognition memory. HubMed – depression


Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.

Proc Natl Acad Sci U S A. 2013 May 13;
Li JZ, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP, Evans SJ, Choudary PV, Cartagena P, Barchas JD, Schatzberg AF, Jones EG, Myers RM, Watson SJ, Akil H, Bunney WE

A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses (“controls”) and 34 patients with MDD. Our dataset covered ?12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders. HubMed – depression


Increased frequency of cluster of differentiation 14 (CD14+) monocytes expressing interleukin 1 beta (IL-1?) in Alzheimer’s disease patients and intermediate levels in late-onset depression patients.

Int J Geriatr Psychiatry. 2013 May 14;
de Lima Torres KC, de Lima GS, Fiamoncini CM, de Rezende VB, de Araújo Pereira P, Bicalho MA, de Moraes EN, Romano-Silva MA

OBJECTIVE: Depression might be a prodromal stage of dementia. Many factors contribute to the etiology of depression and dementia, being inflammation one of those. The present work measured and analyzed immune molecules involved in the innate immunity on cluster of differentiation 14 (CD14+) monocytes trying to investigate any relationship among late-onset depression (LOD) and Alzheimer’s disease (AD). METHODS: Immune molecules were evaluated in monocytes of AD, LOD patients, and controls using flow cytometry. RESULTS: Interestingly, interleukin 1 beta (IL-1?) expressing CD14+ monocytes were increased in AD patients compared with controls. LOD presented intermediate frequency of CD14+ monocytes expressing IL-1? between controls and AD patients. CONCLUSION: Results suggest that an increased frequency of CD14+ monocytes expressing IL-1? level could be a stage marker related to the pathophysiology of dementia process between normal aging and AD. Copyright © 2013 John Wiley & Sons, Ltd. HubMed – depression