Canada

Mutations in the ATP-dependent chromatin remodeller chromodomain, helicase, DNA binding (CHD) 7 are the primary cause of CHARGE syndrome (CS) and have been associated with autism spectrum disorder (ASD). CHARGE is an acronym for the most characteristic features presented by patients: coloboma of the eye, heart defects, atresia chonae, retardation in growth and development, genital abnormalities, and ear defects. Although not included in the diagnostic criteria CS features often include neurological and behavioural problems such as hyperactivity, seizure, intellectual disability and autism. Little is known about the molecular mechanisms that underlie these neurological symptoms. Further, there is no known treatment yet either for patients with CS or for the neurological symptoms shared between CS and ASD. To investigate this, we generated a novel CRISPR/cas9 zebrafish chd7−/− model. We show that chd7 knockout zebrafish larvae exhibit a small head phenotype, defects in craniofacial cartilage development and display aberrant axonal network development. Further the chd7 mutants have less GABAergic neurons and exhibit a hyperactivity behavioural phenotype. Using an unbiased whole transcriptomic approach, we found that the GABAergic neuron defect was at least in part due to the downregulation of a CHD7 target gene, paqr3b and the subsequent upregulation of the MAPK/ERK signalling pathway, which is also dysregulated in CHD7 mutant human cells. Through a phenotype-based screen in chd7−/− zebrafish and C. elegans, we show that the small molecule ephedrine restores MAPK/ERK signalling and improves both GABAergic defects and behavioural anomalies. This work provides insight into the neuropathogenesis in CS and identifies a promising compound for further preclinical studies.

CAN-ACN 2021

Chd7 loss of function in zebrafish impairs GABAergic network development through MEK/ERK signalling: CHARGE syndrome and beyond

gaba neuron

chd7

zebrafish

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Colleagues and Friends:

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.

Highlights of this year’s scientific meeting include invited speakers **Michael Hausser, Franck Polleux, Gwyneth Card, Magdalena Götz**and Brain Prize winner **Huda Zoghbi**. Plenary and parallel symposia, proposed by our members complete our diverse [scientific program.](https://can-acn.org/meeting-2021/program-2021/)

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14th Canadian Neuroscience Meeting from August 23rd-25th

Bipolar disorder (BD) is characterized by alternating cases of depression and mania. Although deviations in neurodevelopment are suspected to contribute to the pathophysiology of BD, the precise molecular underpinnings remain unknown. In cells, calcium plays an influential role in development via signalling cascades. As such, calcium accumulates in the endoplasmic reticulum (ER) from where it can be rapidly released in response to a second messenger. Calcium levels are, therefore, tightly regulated through store-operated calcium entry (SOCE)--a mechanism that promotes calcium influx through ORAI channels when the ER is depleted. Recently, we found striking evidence of aberrant SOCE activity in BD patient-derived induced pluripotent stem cells (iPSCs) differentiated into neural progenitor cells (NPCs) in comparison to iPSC-NPCs derived from healthy control individuals. This led us to discover unsuspected cellular phenotypes. Here, we first summarize calcium imaging data revealing the sharp difference in SOCE between BD patient-derived and control iPSC-NPCs. Second, we show that lower SOCE activity in BD cells correlates with reduced STIM/Orai puncta formation. Third, we reveal decreased proliferation in BD-derived progenitors, which we then connect to a premature neuronal differentiation phenotype affecting migration. Finally, we support this dysregulated development with cerebral organoid modelling. Together, our findings suggest a contribution of SOCE to BD through dysregulation in the neurodevelopment of NPCs.

Neurodevelopmental impact of aberrant calcium mobilization in bipolar disorder patient-derived iPSC-neural progenitor cells

Naked mole-rats (NMRs; Heterocephalus glaber) are among the most hypoxia-tolerant mammals. If and how these organelles tolerate ischemia and how ischemic stress impacts mitochondrial energetics and redox regulation is unknown. We hypothesized that mitochondria fundamentally contribute to in vitro ischemia resistance in NMR brain. To test this, we treated NMR (1-2 years) and CD-1 mouse (14-16 weeks) brain sheets with an in vitro ischemic mimic and evaluated mitochondrial respiration capacity and redox regulation following 15- or 30-mins ischemia or ischemia/reperfusion (I/R). We did not observe differences between sexes (4 males and 4 females) for either species, so we pooled data from both sexes for statistical analysis. We found that, relative to mice, NMR brain largely retains mitochondrial function and redox balance post-ischemia and I/R. Specifically: i) ischemia reduced complex I and II -linked respiration ~50-70% post-ischemia in mice, versus ~20-40% in NMR brain, ii) NMR but not mouse brain maintained relatively steady respiration control ratios and robust mitochondrial membrane integrity, iii) electron leakage post-ischemia was lesser in NMR than mouse brain and NMR brain retained higher coupling efficiency, and iv) free radical generation during and following ischemia and I/R was lower from NMR brains than mice. Overall, these findings support the hypothesis that hypoxia-tolerant NMR brain is also ischemia-tolerant and suggest that NMRs may be a natural model of ischemia-tolerance in which to investigate evolutionarily derived solutions to ischemic pathology.

Naked mole-rat brain mitochondria tolerate in vitro ischemia

Q175/B6 is a knock-in mouse model of Huntington's disease, a neurodegenerative disorder characterized by chorea, loss of motor control and cognitive deficits. The primary site of neurodegeneration in HD is the striatum, a brain region important for motor learning. Studies have revealed motor and cognitive deficits in Q175 mice on the open field, accelerating rotarod and water T-maze tasks. This study aims to replicate these findings in Q175 mice while conducting more detailed analyses on the specific patterns of behaviour during these tests using the DeepLabCut tracking software and the new Behavioral Segmentation of Open Field in DeepLabCut (B-SOiD) machine learning program. 10-month-old Q175 mice engaged in less locomotion and sniffing behaviours and more grooming and rearing as compared to wild-type during the open field. HD mice also showed motor deficits on the rotarod, with a reduced latency to fall and a greater number of foot slips. In mice that used a striatum-dependent response learning strategy during training of the water T-maze, Q175 animals took significantly longer to reach the hidden platform during both training and reversal phases of the task. These findings reveal that Q175 mice show notable motor and cognitive deficits at 10 months of age, including reduced exploratory behaviour and potentially increased anxiety-like behaviours in the open field. Experiments with 3-month-old Q175 mice are also underway. Future studies that examine striatal signalling during performance of these tasks are needed for evaluation of potential therapeutic treatments in HD. Funding provided by the Canadian Institutes of Health Research Foundation grant (Fdn-143210).

Behaviour characterization of the Q175/B6 Huntington's disease mouse model

Huntington disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons involved in motor function degenerate leading to motor & cognitive problems. Dysregulation of synaptic function & Ca2+ handling is common in many neurodegenerative diseases. One level of Ca2+ regulation is at the endoplasmic reticulum (ER), & this regulation is abnormal in HD. The ER is also suggested to be involved in nuclear Ca2+ signaling, & I hypothesize that this signaling pathway is altered in HD. Sigma-1 receptors (S1Rs) - proteins located on the ER - play an important role in Ca2+ regulation & thus gene transcription. Interestingly, activating S1Rs has been shown to normalize this Ca2+ handling & restore synaptic function in HD mouse models. The goal of this project is to determine the link between S1Rs, Ca2+ handling, Ca2+ dependent gene expression, & synaptic function to better understand the pathophysiological mechanisms of HD & to find new potential treatments. Cortico-striatal co-cultures & imaging techniques were used. Our data shows interesting contributions of different Ca2+ channels to nuclear Ca2+ signaling. Ca2+ imaging also suggests impairments in nuclear Ca2+ signaling in HD spiny projection neurons in co-cultures. Furthermore, Activin A, a protein whose expression is Ca2+ dependent, is decreased in HD culture media, & its overexpression normalizes aspects of synaptic function. This project will help us understand the complex pathogenesis of HD & elucidate the roles of key therapeutic targets toward developing disease-modifying treatments.

Calcium handling in striatal neurons in Huntington disease

Chronic stress is a risk factor for anxiety and depression and all are linked to reduced cognitive performance and neuronal atrophy. In these, there is reduced number of GABAergic neurons, reduced GABA release and altered GABAA receptor (GABAAR) functioning. GABAARs contain α subunits that essentially dictate functional outcome: sedation with α1 subunit potentiation, anxiolytic effects with α2/α3 and cognition with α5. Common GABAergic drugs, like benzodiazepines, act at α1/2/3/5-GABAARs but have side effects (sedation, dependence) mixed with mild anxiolytic effects and no cognitive benefits. Therefore, a therapy designed to increase α2/3/5 activity while also devoid of α1 activity has significant clinical relevance and potential. We investigated two enantiomers separately, GL-I-54 and GL-II-73, as well as their combined use as a racemic mixture (termed GL-RM) because of the desirable positive allosteric modulation profile when combined (α2/3/5 and α5 respectively). Using the unpredictable chronic mild stress (UCMS) model in C57BL6 mice (50% female; N=48 per study), anxiolytic, anti-depressant and pro-cognitive effects of GL-RM were assessed after acute or chronic administration. GL-RM reduced stress induced anxiety-like phenotypes and overcame stress induced cognitive deficits. Golgi staining after chronic GL-RM found GL-RM rescued dendritic spine density after UCMS in the PFC and CA1. Results support the value of a therapy with a α2/3/5 GABAAR selective profile to overcome chronic stress-induced mood symptoms and cognitive deficits, and detriments in neuronal morphology.

GABAA receptor positive allosteric modulation has symptomatic and disease modifying effects in a mouse model of chronic stress

Parkinson's Disease (PD) is the second most common neurodegenerative disease in the world. Characterized by motor and non-motor symptoms, PD is associated with the loss of dopaminergic neurons in the Subtantia Nigra (Kalia and Lang, 2015). One of the major pathological hallmarks of the disease is the aggregation of misfolded proteins called alpha-synuclein (α-syn), which will lead to the formation of cellular inclusion known as Lewy bodies (Spillantini et al., 1997). However, how these aggregates disturb neuronal homeostasis leading to neurodegeneration remains elusive. Several studies showed a correlation between alterations of the degradation systems (autophagic or proteasomal), implicated in the protein quality control, and a-syn aggregation (Lehtonen et al., 2019). It is then relevant to know how an alteration of the degradation systems is involved in the pathogenesis of PD. To this purpose, our group recently created a new cellular model in which we control optogenetically and observe in real-time the aggregation of a-syn. This system called the LIPA (Light-Inducible Protein Aggregation) system nicely mimics key features of Lewy bodies (Bérard et al., under review). Using this cellular model, we were able to observe for the first time the effect of LIPA-induced aggregates on the proteasome and autophagy systems in living cells by using specific markers (Menéndez-Benito et al., 2005). Moreover, we also get interested in the inhibition of these systems and the effect on the aggregation. Taken together our observations reveal the impact of autophagy and proteasome dysfunctions in PD pathogenesis.

Impact of alpha-synuclein aggregation on protein degradation systems and its implication in Parkinson's Disease pathogenesis

Stroke is one of the leading causes of death and disability in the world. Unfortunately, there is still no effective therapy to treat the disease. Therapeutic angiogenesis using potent pro-angiogenic agents has already been shown to provide therapeutic benefits. However, the use of such agents is a double-edged strategy because of the increased risk of exacerbation of vascular leakage. Pericytes are specialized mural cells that play a key role in stabilizing the angiogenic vasculature and possess plastic properties, as they are able to differentiate into endothelial cells by reprogramming. Because of their angiogenic and plastic properties, pericytes are an attractive target for developing new interventions to promote neurovascular repair after stroke. Using novel pharmacological and genetic approaches to target pericytes, our results indicate that a recently discovered platelet-derived growth factor, isoform D (PDGF-D), plays an important role in promoting pericyte plasticity contributing notably to a decrease in brain atrophy and a reduction in motor impairment. Furthermore, our data demonstrate that ex vivo pre-conditioned pericytes transplanted intra-nasally migrate to the lesion site and promote its vascularization, which leads to the regression of damage. The overall results therefore suggest that pericytes are an interesting target and a new tool for the development of new therapies against stroke

Exploration of the pro-angiogenic potential of pericytes in the repair of neurovascular unity following cerebrovascular accidents

Background: Experiencing child abuse (CA) is considered as one of the strongest predictors of depression and suicide. Childhood and adolescence are characterized by critical periods (CP) of heightened cerebral plasticity, in which neural circuits can be more easily modified by experience. The closure of these CP is driven by the development of perineuronal nets (PNNs) around certain neurons in the brain. We hypothesize that CA occurring during these CP alters the recruitment and maintenance of PNNs in brain regions involved in emotional regulation. Methods: Well-characterized brain samples of ventromedial prefrontal cortex (vmPFC) from adult depressed suicides with or without a history of CA and matched controls were provided by the Douglas-Bell Canada Brain Bank. Immunofluorescent staining was performed with different combinations of cellular markers (PV, NeuN, Westeria Floribunda Lectin). Fluorescent in situ hybridization (RNAScope®) was performed to identify the phenotype of neurons enwrapped by PNNs. Whole slide and confocal images were analyzed using QuPath and FIJI. Results: As previously reported, PNNs were found to be covering PV+ interneurons and, to a lesser extent, pyramidal neurons (SLC17A7+). CA was found to be associated with higher densities, intensity and coverage of PNNs in the lower layers of the vmPFC. Conclusions: These results suggest that a history CA has a lasting impact on vmPFC circuitry. This may represent a mechanism through which early-life adversity increases vulnerability to psychopathologies and suicide. Experiments are under way to determine the mechanisms underlying this phenomenon, namely through an examination of proximal microglia, which have been shown to be implicated in the regulation and maintenance of PNNs in animal models.

Perineuronal nets in the ventromedial prefrontal cortex of depressed suicides with a history of child abuse

A history of child abuse (CA) strongly increases the lifetime risk of suffering from major depression and predicts an unfavorable course for the illness. Severe CA has been specifically associated with a widespread, robust, and lasting inhibition of oligodendrocyte function, coupled with impaired myelination of small caliber axons in white matter of the human anterior cingulate cortex (ACC). Given that myelin is extremely lipid-rich, one possible explanation for this finding could be a disruption of the lipid profile that composes the myelin sheath. Furthermore, the composition of fatty acids (FA) in myelin phospholipids has been demonstrated to influence its stability and permeability. Therefore, the objective of this study was to quantify and compare FA concentrations in postmortem ACC white matter in the choline glycerophospholipid pool (ChoGpl), a key myelin phospholipid pool, between adult depressed suicides with a history of CA matched depressed suicides without CA and healthy non-psychiatric controls. Total lipids were extracted according to the Folch method and lipids were separated into respective classes using thin-layer chromatography. FA methyl esters from the ChoGpl fraction were quantified using gas chromatography. Our analysis revealed significant differences in FA concentrations between groups, primarily involving the FAs in the arachidonic acid synthesis pathway, which is further corroborated with ACC RNA-sequencing data. Furthermore, the concentration of most FAs was found to decrease with age. These findings are the first to associate a history of early-life adversity with ChoGpl dysregulation in the human brain.

A history of child abuse associates with fatty acid dysregulation in the anterior cingulate cortex of depressed suicides

Interictal epileptiform discharges (IEDs) and Sharp Wave ripples (SWR) are pathological and physiological events in patients with temporal lobe epilepsy. Although these two events may display similar temporal frequency patterns, they carry different energy in different frequency bands. We study a group of epilepsy patients with medically resistant epilepsy (MRE) at the Lawson Research Center at UWO, implanted with SEEG depth electrodes (DE) to identify interictal abnormalities IEDs and differentiate them from SWRs using a new algorithm. The data were cleaned, denoised, montaged and segmented, such as sleep intervals and observed Ictals. The signal waveform and its power were extracted symmetrically in non-overlapping intervals of 500 milliseconds for event detection. Each waveform's power across all detected spikes was computed and clustered based on their energy distributions. The recordings included more than 720 hours of extracellular recordings from three patients with 450 hours of non-sleep data extracted from four hippocampus electrodes anterior and posterior hippocampus. Results indicate that IEDs carrying the largest power in the bands [30-45] Hz, SWR, on the other hand, are distributed between and [25-40] and [90-110] Hz. Our algorithm detected and successfully distinguished IED from SWRs based on their carrying energy during non-sleep periods. The waveforms' energy is more significant in sleep than awake (non-ictal) periods, and was this characteristic was used as an informative feature to cluster these two events.

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Neurodevelopmental impact of aberrant calcium mobilization in bipolar disorder patient-derived iPSC-neural progenitor cells

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