Anxiety Disorders and Major Depressive Disorder (MDD) are among the most prevalent and debilitating psychiatric syndromes. They exhibit extensive comorbidity and overlapping genetic origins, yet their molecular etiology and functional interrelationship are poorly understood. The vulnerability for both types of disorders i greatly exacerbated in early life, indicating that they are primarily developmental disorders. Mounting evidence points to a causal role of deficits in GABAergic transmission for both types of disorders. In particular, MDD is accompanied by reduced function and loss of GABAergic interneurons, reduced GABA concentration most pronounced in the melancholic subtype of MDD, and alterations in the subunit composition of the principal GABA receptors (GABAARs). Moreover, extensive analyses of GABAAR y2 subunit heterozygous mice by our lab suggest that modest developmental deficits in GABAergic transmission through these receptors may be causal for MDD. These mice exhibit behavioral, cognitive and cellular alterations expected of such a model, including endocrine and pharmacologic characteristics of melancholic MDD. Importantly, conditional gene ablation experiments indicate a postnatal developmental origin of this phenotype. Here we propose to use pharmacological manipulation of GABAergic transmission during postnatal development to generate a novel non-genetic mouse model of MDD that uniquely i) mimics a developmental etiology of MDD, ii) allows separation of depression-related from anxiety-related pathology, and iii) leads to a permanent/stable phenotype in adulthood that is amenable to investigation across disciplines (behavioral, cognitive, molecular, neuroanatomical, pharmacological, etc.). Preliminary experiment indicate that treatment of mice with diazepam (DZP) between postnatal day (P)10 and P21 leads selectively to increased anxiety-like behavior. By contrast, DZP treatment from P29-35 leads to selectively increased immobility under stressful conditions, which is the inverse of a pharmacological antidepressant-like effect. Thus, we hypothesize that anxiety- and depression- related behavioral traits are independently controlled by similar mechanisms during distinct postnatal developmental critical periods. We propose to establish P29-35 DZP treated mice as a novel and unique mouse model of MDD that is suited to monitor the developmental molecular sequelae underlying vulnerability to MDD in adulthood, and to distinguish the molecular etiology of MDD from that of heightened anxiety.
In Aim 1 we will more fully establish the depressive like behavioral, endocrine and pharmacologic phenotype of P29-35 DZP treated mice.
In Aim 2 we will use transcriptome analyses of the cingulate cortex of P10-24 and P29-35 DZP treated mice to compare the molecular signature of anxious vs. depressive like brain states. The work proposed will lay the foundation for an in depth analysis of the developmental mechanism underlying vulnerability to MDD.
Major depressive disorder (MDD) represents the second most common cause of total disability with a lifetime prevalence of approximately 12-20% of the population worldwide. The estimated costs to the US economy are over 100 billion dollars annually. Suicide, which is mainly caused by MDD, is the third and fourth cause of death in the 15-24 and 25-44 age groups, respectively. Antidepressant drugs currently used for the treatment of both anxiety and mood disorders act with a delay of several weeks and are effective in about two thirds of patients only, with fewer MDD patients even experiencing remission. Thus, research into the etiology and more effective treatments of MDD should be a major public health priority. We here propose the establishment of a new mouse model of depression that is designed to help understand specifically the developmental aspects of depressive disorders, an aspect that has been largely neglected due to the lack of broadly applicable animal models.
|Ren, Zhen; Sahir, Nadia; Murakami, Shoko et al. (2015) Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice. Neuropharmacology 88:171-9|