Canada

Ferroptosis is a newly identified-form of programmed cell death, which is triggered by excess intracellular iron and deficient antioxidant defense, leading to iron-dependent lipid peroxidation. One molecular pathway of ferroprosis occurs through NCOA4, a shuttle protein that transports cytosolic ferritin to autophagosomes for degradation, resulting in the release of iron from ferritin, which subsequently stimulates lipid peroxidation. In spinal cord injury (SCI), one of the immediate consequences of trauma is rupture of blood vessels. Elevated level of iron due to infiltration of red blood cells to the site of injury increases the possibility that ferroptosis might be involved in secondary damage associated with SCI. However, the role of ferroptosis in SCI remains unclear. We have previously shown that iron accumulation in CD11b+ macrophages is seen rapidly after SCI. We now show increased expression of NCOA4 in the first two weeks after contusion injury in mice. NCOA4 was expressed in microglia/macrophages at the site of SCI lesions and was associated with reduced ferritin. We found that some NCOA4+ cells showed signs of cell death. In addition, protein levels of the antioxidant enzyme glutathione peroxidase 4 (GPX4) remains unchanged after SCI, indicating it may be insufficient to handle increased lipid peroxidation that causes ferroptosis. Treatment with a ferroptosis inhibitor (UAMC-3203), showed a small but significant improvement in locomotor recovery indicated by the BMS score and subscore. These findings indicate that NCOA4 may contribute to ferroptosis mediated iron toxicity in SCI.

CAN-ACN 2021

The role of ferroptosis in iron toxicity following spinal cord injury

iron toxicity

ferroptosis

spinal cord injury

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I am very happy to welcome you to the 14th annual Canadian Neuroscience Meeting, and to the first virtual edition of our meeting. I want to highlight the important work the CAN meeting chair, **Roger Thompson** and co-chair, **Alyson Fournier**, did to put together the great program we are offering this year. Moving to a virtual format required a complete re-design of the program, and both Roger and Alyson did a splendid job in providing us with an appealing and well adapted program for our first virtual event. I wish to thank them for this very important effort.

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14th Canadian Neuroscience Meeting from August 23rd-25th

There is a clear male bias in the prevalence of neurodevelopmental disorders (NDDs). Certain environmental factors have been shown to contribute to the etiology of these NDDs, including exposure to antipyretic drugs. To investigate the molecular mechanisms by which environmental factors may contribute to the male bias in NDDs, we focused on two genetic models that mimic antipyretic drug exposure, namely cyclooxygenase-2 knockin (COX-2-) and COX-2 knockout (COX-2-/-) mice. Illumina and Affymetrix GeneChip arrays were used to profile gene expression in brain samples obtained from COX-2-/- mice during prenatal development. Impaired COX-2 activity was found to downregulate the expression of various neuroimmune markers in the brain of males, whereas markers of ribosomal activity were upregulated in females. Further investigations using Real-Time qPCR on postnatal brain samples also revealed that gene markers linked to distinct subtypes of astrocytes were dysregulated in male and female COX-2- mice. While males exhibited an increased prevalence of neurotoxic A1 astrocytes, females exhibited an increased prevalence of neuroprotective A2 astrocytes. Our findings offer novel insight into the sex-dependent effects of antipyretic drugs, which may ultimately facilitate the discovery of therapeutic targets for NDDs exhibiting a male bias.

The impact of impaired cyclooxygenase-2 activity during mouse brain development: a focus on sex differences

Purpose:Impaired attention is the most common and debilitating cognitive deficit following traumatic brain injury (TBI), leading to rehabilitation barriers and long-term disability. Few studies have explored a standardized and evidence-based rehabilitation pathway for impaired attention after TBI. The aim of this study was to gather expert opinion and identify key elements of rehabilitation pathway for attention deficits after TBI. Methods: First, a survey was conducted among 49 rehabilitation experts from designating teaching hospitals to identify the priority in developing the pathway. Second, evidence and priority-based elements of the pathway were set up for acute and post-acute TBI patients. Thirdly, content validity was evaluated by the Modified Delphi technique on 16 neurorehabilitation professionals. Finally, a qualitative study was conducted, using a focus group interview. Results: 'Successful return to the community' and 'development and dissemination of an attention rehabilitation manual' were academic issues of the highest priority in terms of importance and urgency, respectively. Elements of acute pathway included classification of TBI severity, history and physical exam, clinical testing, assessment and management of postconcussion symptoms and neuropsychiatric sequelae in mild TBI, and disorder of consciousness and post-traumatic confusional state in moderate to severe TBI, cognitive rehabilitation, and outcomes. The post-ac pathway highlighted comprehensive and evidence-based assessment, cognitive rehabilitation programs, medication, and education. Conclusion: Implementation of the rehabilitation pathway for attention impairment after TBI may improve a physiatrists' practice and patients' outcome by decreasing the clinical variances, length of hospi

Key elements of rehabilitation pathway for impaired attention after traumatic brain injury in Korea

Background: Prostaglandin E2 (PGE2) is a bioactive lipid molecule involved in healthy brain development, including neuronal differentiation, migration and plasticity. Exposure to various environmental factors during pregnancy such as infections, inflammation, acetaminophen or misoprostol leads to abnormal PGE2 levels and has been linked to Autism Spectrum Disorders (ASD). We have previously determined that maternal exposure to PGE2 results in differential expression of developmental genes and associated autism-like behaviours, including social and motor deficits, repetitive and anxious behaviours. This study investigates sex-dependent effects of a maternal PGE2-exposure at embryonic day 11 (E11) on the morphology of dendrites of C57bl/6 mice offspring. Methods: The hippocampi of PGE2 and Saline-injected wildtype (WT) male and female offspring at postnatal day 30 were stained using the Golgi-Cox method, followed by confocal microscopy to examine dendritic arborization, length, branch order and the odds of observing dendritic loops. Results: We show that compared to matched WT controls PGE2-exposed males and females (PGE2M and PGE2F) had a statistically greater dendritic arborization closer to the soma, had greater primary branching and increased odds of observing dendritic loops. Also, dendrite length was greater only in PGE2M, compared to the controls. Overall, this study provides new evidence that single maternal PGE2 exposure during the critical time in prenatal development contributes to sex-dependent changes in dendritic architecture in the hippocampus of offspring.

Maternal exposure to prostaglandin E2 affects hippocampal dendritic morphology in C57bl/6 mice offspring - link to autism spectrum disorder (ASD)

Exposure to early adversity increases the risk for non-transmittable diseases, but also psychiatric conditions, and these common developmental risk factors suggest overlapping underlying mechanisms. The dopamine neurons constitute a system underlying the brain response to environmental conditions and functional variations of this system may be linked to long-term unfavorable outcomes in response to early adversity. We created an expression-based polygenic score for the dopamine transporter gene network (ePRS-DAT1) on the prefrontal cortex and striatum, to explore the role of dopamine on the long-term effects of early life adversity on these outcomes. The ePRS-DAT1 reflects genes co-expressed with DAT1 gene in the PFC and STR in a combined manner, being calculated using the effect size of the association between the individual SNPs from those genes and gene expression (GTEx). Using large datasets (UKBiobank for adulthood and ALSPAC for childhood/adolescence), we demonstrate that the ePRS-DAT1 moderates the impact of early life adversity on the risk for both psychiatric and cardiometabolic comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the ePRS suggesting these regions as critical dopaminergic targets for psychiatric/metabolic comorbidities. These results reveal that psychiatric and metabolic comorbidities showed share common developmental pathways and underlying biological mechanisms.

A mesocorticolimbic dopamine gene network moderates the effect of early adversity on the risk for metabolic and psychiatric comorbidities

Neuronal synchrony is often achieved by electrical synapses, which are mediated by intercellular channels, known as gap junctions. Electrical transmission can be modulated by intracellular pathways, including direct effects on connexins/innexins, the pore forming subunits of gap junctions, or alterations to the electrical properties of the postsynaptic neuron. Reproduction in the sea snail, Aplysia, is controlled by electrically coupled bag cell neurons. Upon brief synaptic input, these neuroendocrine cells undergo a synchronous burst of action potentials, known as the afterdischarge, culminating in the secretion of egg-laying hormone into the bloodstream. Near the start of the afterdischarge, cAMP levels are elevated. While it is well-established that cAMP inhibits K+ channels, thereby increasing excitability, nothing is known of the effects of this second messenger on electrical transmission in bag cell neurons. Here, we used pairs of cultured bag cell neurons and whole-cell recording to investigate the impact of cAMP on electrical coupling. Presynaptic action potentials consistently evoked postsynaptic electrotonic potentials, while presynaptic hyperpolarization was transferred accordingly to the postsynaptic cell. Delivery of a membrane-permeable cAMP analogue increased the electrotonic potential by ~25%, which was accompanied by a similar change in coupling coefficient. In addition, input resistance was also augmented by ~100%. These outcomes suggest cAMP may enhance electrical transmission, and as a consequence, influence synchronous firing during the afterdischarge.

Cyclic AMP influences electrotonic transmission between coupled neuroendocrine cells

The adult subventricular zone (SVZ) niche contains neural stems cells (NSCs) that maintain and regenerate the brain by producing neurons, astrocytes and oligodendrocytes throughout life. Directly adjacent to the SVZ is the striatum; a region that is important in movement regulation and is rich in GABAergic neurons. While striatal neurons are known to project into NSC-rich SVZ niche, the significance of striatal neuron - SVZ NSC cell-cell communication is not currently known. I hypothesize postnatal SVZ NSCs fates are regulated by striatal neurons. To address this question, I cultured postnatal primary murine SVZ NSCs in control media or media conditioned by primary striatal neurons. My data show striatal neurons secrete soluble molecules that instruct SVZ NSCs to differentiate into oligodendrocytes and neurons without affecting astrocyte formation or NPC proliferation. To further investigate the pro-oligodendrogenic influence of the striatal neuron secretome, we cultured SVZ oligodendrocyte precursor cells (OPCs) in media conditioned by striatal neurons. Our data demonstrate striatal neuron conditioned media causes an increase in OPC differentiation into oligodendrocytes. Using RNA-seq datasets of purified striatal neurons and SVZ NSCs, I then computationally predicted over 80 striatal neuron ligands that have the potential to regulate SVZ NSC biology. In summary, my results suggest striatal GABAergic neurons may play an important role in regulating SVZ NSCs. Future work will determine which striatal neuron ligands are responsible for the observed pro-neurogenic and -oligodendrogenic effects and identify the in vivo significance of these molecules in the SVZ niche.

Striatal neurons regulate neural stem cell fates through secreted molecules

Dendritic spines are postsynaptic structures that arise from dynamic protrusions. Spine formation is a critical facet of synapse formation and aberrant spine properties are a hallmark of many neurodevelopmental disorders. Our lab previously found that expression levels of channel-forming protein pannexin 1 (PANX1) decrease during the period of spine formation. Panx1 knockout (KO) increased spine density and PANX1 overexpression reduced their stability and density. Unpublished results from our lab reveal that probenecid, a PANX1 blocker and Health Canada- and FDA-approved drug, recapitulated the effects of Panx1 KO. Early postnatal acute and chronic administration of probenecid led to increased somatosensory layer 5 cortical neuron spine density in situ. The current study aims to investigate the mechanism underlying probenecid regulation of dendritic spines, and capitalizes on our previous finding that probenecid interferes with a physical interaction between PANX1 and microtubule-stabilizing protein. To gain insight into spine cytoskeleton dynamics during development, we treated neurons with probenecid and imaged microtubule and actin dynamics within spines using microtubule plus-end binding probe EB3-GFP and actin-binding protein Lifeact. In parallel, we monitored spine dynamics using membrane-bound mCherry to understand the relationship between microtubule and actin dynamics and overall spine movement. This work will advance our understanding of dendritic spine development with implications for understanding the cellular mechanisms underlying neurodevelopmental diseases.

Probing dendritic spine cytoskeleton dynamics with the pannexin 1 blocker probenecid

Spinal cord injury (SCI) results in neurodegeneration and damage to the spinal neural circuitry. To date, effective neuronal replacement and functional restoration of spinal circuit remain challenging. Transplantation of neural precursor cells (NPCs) offers a promising approach for neuronal replacement in SCI. However, our studies indicate limited neurogenesis by transplanted NPCs in the hostile milieu of SCI. We identified that injury-induced upregulation of chondroitin sulfate proteoglycans (CSPGs) hinders survival and integration of engrafted NPCs after SCI by signaling through two main receptors, LAR and PTP-σ. Here, we have evaluated the therapeutic potential of co-blocking LAR and PTP-σ by ILP and ISP peptides, respectively, in conjunction with transplantation of human directly reprogrammed NPCs (drNPCs) with the capacity to generate spinal neurons. Our in vitro studies confirmed ILP/ISP co-treatment restores the inhibitory effects of CSPGs on drNPCs and promotes their neuronal differentiation, maturation, and synaptogenesis. In rat SCI, systemic delivery of ILP/ISP significantly promoted long-term survival and biodistribution of human drNPCs, enhanced their neuronal differentiation and complexity, and functional recovery after SCI. Our transcriptomic analysis identified that CSPGs impede neuronal differentiation by inactivating the Wnt/β-catenin pathway, which was verified in our in vitro studies. Altogether, we have developed a new targeted, translationally feasible strategy with the potential to optimize neuronal replacement and functional recovery after SCI.

Suppressing CSPGs receptors enhances spinal specific neuronal replacement by human directly reprogrammed neural precursor cells and improves functional recovery after spinal cord injury

Huntington disease (HD) is monogenic and caused by a CAG repeat expansion in the IT15 gene, which results in the production of a mutant huntingtin protein (mHTT). In addition to the production of this pathogenic variant, HD patients generate half the amount of wild type huntingtin (wtHTT). Although wtHTT has a well-established role in neurodevelopment, as its knockout is embryonic lethal, its exact role in the adult brain is not well understood. Recent literature suggests a major role for wtHTT in synaptic function in adult neurons, specifically loss of wtHTT impairs presynaptic vesicle release as well as postsynaptic receptor localization. We hypothesized that these synaptic impairments may lead to defects in NMDAR-dependent long term potentiation (LTP)-induced changes in hippocampal wtHTT-lowered neurons. Chemical LTP (cLTP) was induced using glycine in primary hippocampal cultured neurons and wtHTT levels were lowered by siRNA application. Both presynaptic synaptophysin (SYP) and postsynaptic PSD-95 were labelled by immunofluorescence. Using super-resolution microscopy, we quantified the density of SYP and PSD-95 puncta from individual dendrites at the nanoscale level. cLTP induction revealed an activity-dependant decrease in SYP, but not PSD-95, density in wtHTT-lowered cells. These findings indicate a potential switch from synaptic potentiation to depression and subsequent loss of synapses during hippocampal NMDAR activation due to wtHTT lowering. Understanding these outcomes is essential as many HD genetic therapies in development further lower patient wtHTT levels.

Huntingtin reduction unmasks an active form of NMDAR-dependent synapse loss

Disruptions in the Cntnap2 gene are known to cause language impairments and symptoms associated with autism spectrum disorder (ASD) in humans. Importantly, knocking out this gene in rodents results in ASD-like symptoms that involve auditory processing deficits. This study used in vitro electrophysiology to examine alterations at a cellular level in the auditory cortex of a Cntnap2-/- rat model, hypothesizing that Cntnap2 is essential for maintaining intrinsic neuronal properties and excitability in the auditory cortex. Whole-cell patch clamp recordings were performed in brain slices from juvenile (P8-12 and P18-21) and adult (P70-90) wildtype (Cntnap2+/+) and knockout (Cntnap2-/-) rats. Intrinsic membrane properties, spontaneous EPSCs and firing patterns of cortical pyramidal cells were assessed. Action potentials were significantly larger in Cntnap2-/- rats at P8-12 and P18-21, and Cntnap2-/- rats at both P8-12 and P18-21 exhibited smaller half-widths compared to wildtypes. Compared to wildtypes, Cntnap2-/- rats exhibited larger sEPSCs at P8-12, but they were smaller at P18-21 and P70-90. The Cntnap2-/- rats also had higher sEPSC frequencies at P70-90, but there were no differences at the younger ages. These results indicate that intrinsic cell properties and activity are altered in Cntnap2-/- rats, but these differences are not consistent across the ages. These experiments will provide novel insights into how Cntnap2 impacts auditory processing at a cellular level, and shed light on the neural mechanisms underlying altered auditory processing seen in Cntnap2-/- rats.

Next from CAN-ACN 2021

The impact of impaired cyclooxygenase-2 activity during mouse brain development: a focus on sex differences

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