Molecular Mechanisms of Synapse Development and Plasticity

National Institute Of Mental Health

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Abstract

1. BAX regulates dendritic spine development via mitochondrial fusion. Mitochondria are organelles in eukaryotic cells that carry out multiple vital functions, such as aerobic respiration, regulation of intracellular Ca2+, and apoptosis. Mitochondria are of particular importance to neurons in which they not only supply ATP for energy-consuming synaptic transmission but also regulate synaptic plasticity via the non-apoptotic function of caspases and shaping the kinetics of Ca2+ transients. The proper content and subcellular distribution of mitochondria in dendrites are essential for synapse formation and the morphogenesis of dendritic spines. Mitochondria exist as tubules of variable sizes and undergo dynamic remodeling through fusion and fission. The balance between fusion and fission is essential for the homeostasis and quality control of mitochondria. While mitochondrial fission has been implicated in spine development, the significance of mitochondrial fusion to spine development, however, has yet to be determined. BAX is a Bcl-2 family protein that functions in synaptic plasticity and mitochondrial fusion. In this study, we explored the role of BAX in dendritic spine development. We analyzed mitochondria and dendritic spines in hippocampal slices prepared from wild-type and BAX knockout mice. We found that spine density and dendritic ATP are reduced in the hippocampal neurons of BAX knockout mice and that these decreases are attributed, at least in part, to deficient mitochondrial fusion. These findings reveal that BAX-mediated mitochondrial fusion is essential for dendritic spine development and ATP production. 2. Mitophagy in the basolateral amygdala mediates increased anxiety induced by aversive social experience. Anxiety is sustained fear for potential future and anticipated threats. At least one-third of individuals with anxiety disorders do not achieve sustained remission by using the current first-line medications. Anxiety can be increased by chronic stress. Chronic stress has a significant impact on brain mitochondria in animals. However, it has yet to be determined if the mitochondrial disturbance is a cause or consequence of behavioral alterations associated with stress, in particular psychosocial stress. Mitochondrial quantity in neurons is governed by two opposing processes, mitochondrial biogenesis and mitophagy. PINK1 (PTEN-induced putative kinase protein 1) and Parkin (an E3 ubiquitin ligase) are two key proteins involved in mitophagy. Mutations in PINK1 and Parkin are associated with Parkinsons disease. In this study, we investigate the role of mitochondria in chronic social defeat (CSD)-induced behavioral alterations. We show that CSD causes mitochondrial impairments, which lead to activation of the PINK1-Parkin mitophagy pathway in the amygdala. The consequent excessive elimination of mitochondria causes weakening of the BLA-adBNST (anterodorsal bed nucleus of the stria terminalis) synapses, thereby increasing anxiety-like behaviors. This study uncovers a previously unsuspected role of mitophagy in the anxiety increase associated with stress. 3. Opposing effects of NMDA receptor antagonists on early life stress-induced aggression in mice. Recurring and excessive violent aggression is a serious concern for society and is reliably predicted by early life stress. Unfortunately, current pharmacological treatment options for excessive and recurring aggression are limited, largely ineffective, and far from preventative. Given the critical societal need for such drugs, a more thorough investigation is required. A promising pharmacological target is the N-methyl-d-aspartate receptor (NMDAR) which has been shown to regulate alcohol-induced aggression escalation, short-term aggressive behavior after early life stress, and recurring attack behavior after aggression priming. While antagonists of NMDARs have been effective at treating aggression in humans and mice, these effects are nuanced and complex. For example, the NMDAR noncompetitive antagonist ketamine, which reduces aggression associated with posttraumatic stress disorder (PTSD) in humans, decreases aggression in socially isolated (SI) mice at high doses but increases it at low doses. The low-affinity NMDAR antagonist memantine, which reduces aggression in Alzheimer's disease and dementia patients, reduces aggression in mice injected with morphine, but heightens aggression when coupled with ethanol. These results indicate that different NMDAR antagonists have distinct effects on aggression, which are highly context-specific and dose-dependent. In this study, we examined whether NMDAR antagonism could suppress early life stress-induced aggression. We began by confirming previous results showing that SI during early adolescence followed by acute physical stress in the form of noncontingent foot shock (FS) during late adolescence is required for prolonged increases in excessive aggression when measured seven days later. We then examined whether systemic injections of MK-801, memantine, or ketamine could suppress early life-stress-induced aggression when applied after SI and before FS. Interestingly, we found that MK-801 and memantine suppressed the aggression increase when measured seven days later, while ketamine surprisingly increased aggression when measured seven days later. These results indicate that different NMDAR antagonists have distinct effects on aggressive behavior and demonstrate the need for greater care when using NMDAR drugs to treat excessive aggression. 4. Working memory and reward increase the accuracy of animal location encoding in the medial prefrontal cortex. Animals need to locate themselves in the environment to navigate safely, avoid predators, and forage for food. Perception of spatial location not only is critical for survival but also informs complex behaviors and high-level cognitive processes. Spatial locations can be represented by the firing of spatially tuned cells in rodents, such as place cells in the hippocampus. Spatially tuned cells are also present in human brains within the hippocampus and its surrounding medial-temporal-lobe areas.The medial prefrontal cortex (mPFC) has also been implicated in spatial navigation. The goal of this study is to test whether working memory and reward influence the encoding of animal location in the mPFC. To address this question, we interrogated the properties of spatial encoding in the mPFC by recording mPFC neurons in several spatial tasks that have different requirements for working memory and reward-seeking. Our study shows that although individual mPFC neurons exhibit location-selective firing, their spatial tuning curves are broad. The population activity of mPFC neurons encodes the animal location more reliably. The accuracy of population coding is positively influenced by working memory and reward-seeking.