FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function

Apoptosis is crucial for the correct development of the nervous system. In adulthood, the same protein machinery involved in programmed cell death can control neuronal adaptiveness through modulation of synaptic pruning and synaptic plasticity processes. Caspases are the main executioners in these molecular pathways, and their strict regulation is essential to perform neuronal remodeling preserving cell survival. FAIM-L and SIVA-1 are regulators of caspase activation. In this review we will focus on FAIM-L and SIVA-1 as two functional antagonists that modulate non-apoptotic caspase activity in neurons. Their participation in long-term depression and neurite pruning will be described in base of the latest studies performed. In addition, the association of FAIM-L non-apoptotic functions with the neurodegeneration process will be reviewed.

An Enriched Environment Reduces Chronic Stress-Induced Visceral Pain Through Modulating Microglial Activity in the Central Nucleus of the Amygdala

Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders, however, the underlying mechanisms of CBT remain to be explored. Previously we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We sterotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days following CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment and the expression of synaptic pruning-related signals C1q, C3 and C3R were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared to control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.

Can the Imbalance Between Neurotrophic and Apoptotic Proteins be the "Beware the Ides of March" for Unaffected Relatives of Schizophrenia Patients?

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that the siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which is tpa-BDNF pathways proteins and thought to play a role in synaptic pruning as a possible endophenotype of schizophrenia. Forty drug-naïve patients with first-episode psychosis (FEP) matched for age, gender and level of education, 40 unaffected siblings (UAS) of patients with FEP and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway, pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiateFEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the healthy control group with statistically significant differences between all 3 groups. The plasma levels of pro-BDNF in the healthy control group were similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data Support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ, and this imbalance could be an endophenotype of the disease.

Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1

Growing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation as well as synaptic transmission and plasticity. Iba1 (ionized Ca+2-binding adapter protein 1), encoded by the Allograft inflammatory factor 1 (Aif1) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global, Iba1-deficient (Aif1−/−) mice to characterize microglial activity, synaptic function, and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1−/− microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1−/− brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1−/− mice displayed deficits in the excitatory synapse number and synaptic drive assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1−/− mice. During early postnatal development, when synapse formation is a predominant event in the hippocampus, the excitatory synapse number was still reduced in Aif1−/− mice. Together, these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in adulthood and correlated with significant behavioral changes in adult Aif1−/− mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuroglia developmental processes that may deeply influence behavior.

Preventing adolescent synaptic pruning in mouse prelimbic cortex via local knockdown of α4βδ GABAA receptors increases anxiety response in adulthood

Anxiety is increasingly reported, especially in adolescent females. The etiology is largely unknown, which limits effective treatment. Layer 5 prelimbic cortex (L5PL) increases anxiety responses but undergoes adolescent synaptic pruning, raising the question of the impact of pruning on anxiety. Here we show that preventing L5PL pruning increases anxiety in response to an aversive event in adolescent and adult female mice. Spine density of Golgi-stained neurons decreased ~ 63% from puberty (~ PND35, vaginal opening) to post-puberty (PND56, P < 0.0001). Expression of α4βδ GABAA receptors (GABARs) transiently increased tenfold in L5PL at puberty (P < 0.00001), but decreased post-pubertally. Both global and local knockdown of these receptors during puberty prevented pruning, increasing spine density post-pubertally (P < 0.0001), an effect reversed by blocking NMDA receptors (NMDARs). Pubertal expression of the NMDAR-dependent spine protein kalirin7 decreased (50%, P < 0.0001), an effect prevented by α4 knock-out, suggesting that α4βδ-induced reductions in kalirin7 underlie pruning. Increased spine density due to local α4 knockdown at puberty decreased open arm time on the elevated plus maze post-pubertally (62%, P < 0.0001) in response to an aversive stimulus, suggesting that increases in L5PL synapses increase anxiety responses. These findings suggest that prelimbic synaptic pruning is necessary to limit anxiety in adulthood and may suggest novel therapies.

Macrophages Are Dispensable for Postnatal Pruning of the Cochlear Ribbon Synapses

Ribbon synapses of cochlear hair cells undergo pruning and maturation before the hearing onset. In the central nervous system (CNS), synaptic pruning was mediated by microglia, the brain-resident macrophages, via activation of the complement system. Whether a similar mechanism regulates ribbon synapse pruning is currently unknown. In this study, we report that the densities of cochlear macrophages surrounding hair cells were highest at around P8, corresponding well to the completion of ribbon synaptic pruning by P8–P9. Surprisingly, using multiple genetic mouse models, we found that postnatal pruning of the ribbon synapses and auditory functions were unaffected by the knockout of the complement receptor 3 (CR3) or by ablations of macrophages expressing either LysM or Cx3cr1. Our results suggest that unlike microglia in the CNS, macrophages in the cochlea do not mediate pruning of the cochlear ribbon synapses.

The information theory of developmental pruning: Optimizing global network architectures using local synaptic rules

During development, biological neural networks produce more synapses and neurons than needed. Many of these synapses and neurons are later removed in a process known as neural pruning. Why networks should initially be over-populated, and the processes that determine which synapses and neurons are ultimately pruned, remains unclear. We study the mechanisms and significance of neural pruning in model neural networks. In a deep Boltzmann machine model of sensory encoding, we find that (1) synaptic pruning is necessary to learn efficient network architectures that retain computationally-relevant connections, (2) pruning by synaptic weight alone does not optimize network size and (3) pruning based on a locally-available measure of importance based on Fisher information allows the network to identify structurally important vs. unimportant connections and neurons. This locally-available measure of importance has a biological interpretation in terms of the correlations between presynaptic and postsynaptic neurons, and implies an efficient activity-driven pruning rule. Overall, we show how local activity-dependent synaptic pruning can solve the global problem of optimizing a network architecture. We relate these findings to biology as follows: (I) Synaptic over-production is necessary for activity-dependent connectivity optimization. (II) In networks that have more neurons than needed, cells compete for activity, and only the most important and selective neurons are retained. (III) Cells may also be pruned due to a loss of synapses on their axons. This occurs when the information they convey is not relevant to the target population.