Canada

Background: The in vitro characterization of transitional microglial states in the context of neurodegeneration is lacking; therefore, we report a novel classification system that tracks microglial activation state and potential neurotoxicity. Furthermore, we were interested in the role of leucine rich repeat kinase2 (LRRK2) in this regard, given its importance in inflammatory processes and that it is implicated in Parkinson&#39;s Disease (PD). Methods: Differentiated neuronal SH-SY5Y cells were pre-stressed with sub-toxic levels of glutamate prior to co-culture with lipopolysaccharide-activated microglial BV2 cells or primary microglia. Both transwell co-cultures and mixed live-cell imaging was used to asses microglial transition through various morphological phenotypes and their impact on SH-SY5Y cells. Results: Healthy neurons were resistant to microglial-mediated inflammation but pre-stressed neurons were highly susceptible. Pre-stressed neurons actively recruited microglia, which expressed high levels of oxidative stress and formed large cellular aggregates. LRRK2 kinase and WAVE2 inhibitors (MLi2 and CK-869, respectively) stunted microglial activation and reduced pro-inflammatory cytokines. Conclusion: LRRK2 and WAVE2 may be important mediators in microglial-induced neurotoxicity and these data may be mechanistically important for better understanding neuron-microglial crosstalk and its role in neurodegenerative conditions.

CAN-ACN 2021

LRRK2 mediated microglial phenotype and neurotoxicity in a novel two-hit in vitro model of neurodegeneration

priming

neurodegeneration

microglia

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Background: The in vitro characterization of transitional microglial states in the context of neurodegeneration is lacking; therefore, we report a novel classification system that tracks microglial activation state and potential neurotoxicity. Furthermore, we were interested in the role of leucine rich repeat kinase2 (LRRK2) in this regard, given its importance in inflammatory processes and that it is implicated in Parkinson's Disease (PD). Methods: Differentiated neuronal SH-SY5Y cells were pre-stressed with sub-toxic levels of glutamate prior to co-culture with lipopolysaccharide-activated microglial BV2 cells or primary microglia. Both transwell co-cultures and mixed live-cell imaging was used to asses microglial transition through various morphological phenotypes and their impact on SH-SY5Y cells. Results: Healthy neurons were resistant to microglial-mediated inflammation but pre-stressed neurons were highly susceptible. Pre-stressed neurons actively recruited microglia, which expressed high levels of oxidative stress and formed large cellular aggregates. LRRK2 kinase and WAVE2 inhibitors (MLi2 and CK-869, respectively) stunted microglial activation and reduced pro-inflammatory cytokines. Conclusion: LRRK2 and WAVE2 may be important mediators in microglial-induced neurotoxicity and these data may be mechanistically important for better understanding neuron-microglial crosstalk and its role in neurodegenerative conditions.

poster

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.

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Shernaz Bamji

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14th Canadian Neuroscience Meeting from August 23rd-25th

Subiculum pyramidal neurons form the main output of the hippocampus, and are classically viewed as giving rise to memory by branched structures that receive proximal and distal input. Here, we identified a sparse pyramidal cell subpopulation within the subiculum that diverges from classical pyramidal neuron characteristics across connectivity, morphology, and intrinsic activity. Via transcriptomics, we identified a sparse excitatory neuron population that occupies the deepest layer of the subiculum, and generated a new transgenic mouse line that allows cre-mediated cell-type-specific access of these deep cells. Combining this transgenic line with cell-type-specific viral tracing tools, we discovered that this deep cell population forms dedicated projections to the anterior thalamic nuclei, a key brain region in spatial working memory. Moreover, these deep cells lack radial oblique dendrites typical of classical subiculum pyramidal cells. Motivated by this unique local and long-range structure of these cells, we investigated potential differences in intrinsic function via whole cell patch-clamp recordings. Recording results revealed that these deep cells exhibited an increased input resistance compared to classical pyramidal cells in the subiculum. Altogether, our data provides evidence for a previously unknown subiculum pyramidal cell subtype that exhibits unique structural and intrinsic characteristics, which could indicate a potentially specialized role in spatial memory. Future work will be integral to identifying the functional correlates of this atypical population.

Atypical subiculum pyramidal neurons form dedicated projections and exhibit morphological and electrophysiological differences

Synaptic plasticity, characterized by long-term potentiation(LTP) and long-term depression (LTD), is an important physiological phenomenon that is thought to underlie the mechanism of learning and memory formation. Dysregulation in synaptic plasticity is associated with various neurological disorders. Successful treatments to enhance learning have been hard to target to the lack of understanding in the mechanisms underlying synaptic plasticity. Synaptopodin (SP), a novel actin-associated protein, was found to be an important regulator of synaptic plasticity and learning. SP is found in a subset of dendritic spines, namely the larger, functionally stronger synapses. It is associated with an intracellular organelle the spine apparatus which is responsible for calcium release from internal calcium stores and local protein synthesis. Previous research demonstrated that SP knock-out (SPKO) mice have impaired NMDA- dependent LTP and spatial learning ability but no change in NMDA-dependent LTD. mGluR-LTD is another form of LTD in the hippocampus and its expression mechanisms are much less understood than NMDA-LTD. mGluR-LTD requires IP3R- dependent calcium signaling and protein synthesis-dependent pathway. Its dysregulation has been associated with learning deficit in many neurological diseases, in particular, Fragile X syndrome, the most prevalent neurodevelopmental disorder. Using SPKO mice, we found a reduction in mGluR-LTD compared to wildtype mice. We report that mGluR-LTD - through activation of mGluR1 but not mGluR5 - drives selective loss of the larger more stable excitatory synapses distinguished by the lack of SP. We also observed a signifcant reduction of IP3R in SPKO spines. These findings identify spines that harbor SP as the cellular locus of mGluR-LTD.

Synaptopodin, a novel actin-associated protein, plays important role in mGluR-LTD

Latrophyllins belong to the family of adhesion G protein-coupled receptors, capable of binding to actin-associated scaffold proteins. They are expressed in various tissues, suggesting that they might participate in biological processes that are ubiquitous. Here we focus on actin cytoskeleton dynamics to explore the role of latrophilins in mammalian cells. Overexpression of each latrophilin isoform comparably increased cell volume while modifying the net profile of F-actin-dependent cell structures, as evaluated by confocal microscopy analysis. Latrophilin deletion mutants evidenced that direct coupling to the intracellular machinery was a requirement for modulating cell structures. The association between latrophilins and the actin cytoskeleton was detected by co-immunoprecipitation assays and corroborated with immunocytochemistry analysis. Consistent with the destabilization of F-actin structures, latrophilin isoforms constitutively induced a prominent increase in the activity of actin depolymerizing factor, cofilin, evaluated by western blot assays. Intercellular adhesion events stabilized by heterophilic Teneurin-4 trans-interactions disrupted latrophilin colocalization with F-actin and led to an isoform-specific rescue of cell extensions. Therefore, we found that constitutive signaling of latrophyllins and their activation by ligand directly involves the actin cytoskeleton machinery

Study of the mechanisms involved in the remodeling of the actin cytoskeleton induced by Latrophyllins 1,2 and 3

Aging is associated with cognitive decline and memory loss in humans. In rats, age-associated impairment of spatial and olfactory learning has been observed. We investigated how neuronal excitability changes during aging both in pyramidal neurons of the piriform cortex (PC) and in the CA1 layer of the hippocampus, two key areas involved in these behaviors. In young (<5 months old) and aging Sprague-Dawley rats (>18 months old), we used whole-cell patch clamp recording to measure intrinsic electrophysiological properties of pyramidal neurons in each region. To preserve the health of slices, rats were intracardially perfused with cold and bubbled (95% O2, 5% CO2) artificial cerebrospinal fluid prior to dissection and slicing. Sagittal slices were incubated in N-methyl-D-glucamine (NMDG)-based recovery solution for 10 minutes, and then transferred to a HEPES buffered holding solution for full recovery. In whole-cell configuration, cells were injected with depolarizing currents to generate a current-voltage (I-V) relationship, where somatic and action potential (AP) properties were measured. In addition, current was injected to characterize slow afterhyperpolarization (AHP). In both regions, AP threshold was significantly higher for aged rats, with larger fast AHP. Aged hippocampal neurons also displayed a reduced excitability, along with higher input resistance and a significantly larger slow AHP. These differences in intrinsic neuronal function may contribute to underlying age-related mechanisms of reduced synaptic plasticity and overall cognitive decline.

The effects of aging on intrinsic properties of pyramidal neurons in the piriform cortex and hippocampus

Despite demonstrations that a number of different types of sensory stimuli can evoke calcium responses in glia, a comprehensive understanding of the mechanisms underlying the generation of these events in intact animals remains limited. To thoroughly investigate the signalling pathways mediating the recruitment of glial activation during visual stimulation, we generated Xenopus laevis tadpoles which express GCaMP6s in all cells of the brain and used in vivo two-photon microscopy to simultaneously image both neurons and glia in the developing retinotectal system of intact animals. Using a systematic combination of visual stimulation and pharmacological manipulation during live imaging, we were able to demonstrate that radial astrocytes in the optic tectum are highly responsive to visual stimulation, and that visually-evoked responses in these glia continue to occur following broad blockade of all glutamate receptors and the subsequent silencing of post- but not pre-synaptic neuronal activity. We observed that visually-evoked responses in radial astrocytes are silenced following the additional blockade of either glutamate transporters or sodium-calcium exchangers (NCX) and that the blockade of NCX alone is sufficient to prevent radial astrocytes from responding to visual stimulation, suggesting NCX may play a pivotal role in glia during early development of the visual system.

Visually-evoked calcium transients in glia are mediated by sodium-calcium exchangers in the developing retinotectal system

Growing evidence indicates that during early stages of Alzheimer's disease (AD) abnormal brain activity occurs due to disruption of GABAA-mediated transmission. While disrupted GABAA signaling may result from several mechanisms, recent evidence points to deficits in the potassium-chloride cotransporter KCC2, responsible for maintaining low intracellular chloride in neurons to maintain robust inhibition. In this study, we validate whether KCC2 is downregulated in two transgenic mouse lines that develop AD-like amyloid-beta pathology and symptoms. Further, we examine whether by restoring KCC2 function we can alleviate deficits associated with AD. We found a decrease in the global and membrane protein levels of KCC2 in layer II/III of the prefrontal cortex of 5xFAD mice. In addition, ex vivo chloride imaging revealed impaired Cl- transport in the 5xFAD mice. Moreover, the power of hippocampal gamma oscillations was decreased in the APPNL-G-F mice, as predicted from deficits in KCC2. Consistent with this prediction, treatment with CLP290, a KCC2 activity enhancer, restored the power of the higher band gamma oscillations. Finally, short-term administration of CLP290 in the 5xFAD mice improved spatial memory in the Morris Water Maze (MWM) test whereas it improved learning performance in the MWM and episodic memory in the Contextual Fear Conditioning test in the APPNL-G-F mice as compared to vehicle-treated controls. These results indicate that KCC2 may be a viable target for reversing deficits in GABAA-mediated inhibition in AD and attenuating several symptoms associated with AD pathology.

Enhancing the potassium chloride co-transporter KCC2 reverses functional deficits associated with Alzheimer's disease-related mutations in mice

Early life seizures (ELS) are often refractory to conventional anticonvulsant treatments, and can result in later life epilepsy and severe cognitive deficits. Our recent study demonstrated that ELS acutely reduced the excitatory synaptic inputs onto hippocampal fast-spiking (FS) interneurons through affecting presynaptic neurotransmitter release, which plays a crucial role in ELS pathophysiology. Thus, enhancing excitatory synaptic afferents onto FS interneurons will represent a logical approach to normalize the function of FS interneurons in ELS. BDNF regulates excitatory circuit development in FS interneurons through TrkB receptors. Therefore, we hypothesize that activation of TrkB receptors will alleviate ELS-induced dysfunction of excitatory afferents onto hippocampal FS interneurons. ELS were induced in P10-12 mice. We found that activation of TrkB receptors using a partial TrkB receptor agonist, LM22A-4, significantly increased the frequency of AMPA receptor mediated sEPSCs, but not sEPSC amplitude in CA1 FS interneurons in slices from 1 hour post-ELS mice, through increasing the probability of neurotransmitter release as evidenced by increased paired pulse ratio of evoked AMPAR EPSCs. Furthermore, LM22A-4's effects were abolished by co-administration of the TrkB receptor antagonist, ANA-12. These data strongly support a critical role of TrkB receptors in mediating ELS-induced dysregulation of hippocampal fast-spiking interneurons, and provide a potential therapeutic option for early life epilepsy.

Trkb receptor activation alleviates early seizure-induced dysfunction of hippocampal fast-spiking interneurons

Studies of perception and cognition in schizophrenia (SCZ) show neuronal background noise (ongoing activity) to intermittently overwhelm external stimulus processing. This increased relative noise results in temporal imprecision and higher variability of behavioral responses. What, however, are the neural correlates of temporal imprecision in SCZ behavior? We report EEG decrease in signal-to-noise ratio (SNR) in two SCZ groups (but not in depression) in broadband, theta, and alpha bands. SCZ also show lower intertrial phase coherence (ITPC) relative to stimulus onset in theta which, as computational simulations show, is due to phase-based temporal desynchronization. Reduced SNR and ITPC are related and show a relationship to temporal precision on the behavioral level, namely reaction times. In conclusion, we demonstrate how diagnostic-specific temporal imprecision in SCZ neural activity - reduced relative signal strength and phase coherence - mediates temporal imprecision on the behavioral level. Temporal imprecision may underlie the altered neuro-cognitive processing in SCZ.

It's in the timing: reduced temporal precision in neural activity of schizophrenia

Disturbance of the central serotonin system has long been thought of playing a leading role in major depressive disorder. The main serotonergic nucleus of the brain, the dorsal raphe nucleus (DRN), integrates inputs from multiple brain regions, a large fraction of which is coming from the lateral hypothalamic area (LHA). In this study, we have examined whether plasticity at the LHA-DRN pathway contributes to the development of depressive or resilient phenotypes in mice undergoing chronic social stress. To activate LHA terminals in DRN, an AAV-ChR2-YFP was injected in the LHA of 6 weeks old C57BL/6J male mice. Two weeks later, these mice were subjected to chronic social defeat stress (CSDS) protocol. 24-h after CSDS, mice were classified as either susceptible or resilient when evaluated in a social interaction test, and acute brain slices encompassing the DRN were prepared. During whole-cell patch-clamp recordings of DRN neurons, 5 ms blue light pulses were delivered to activate LHA axons terminals, and postsynaptic currents were measured to investigate pre- and postsynaptic plasticity. In resilient mice, we found a significant increase in paired-pulse ratio at GABAergic synapses, indicating the decreased GABA release probability. In susceptible mice, we measured an important trend toward a decrease in the AMPAr/NMDAr ratio, indicating synaptic depression at the LHA-DRN pathway caused by CSDS. These results suggest that synaptic dysfunction may play an important role in the behavioral phenotype found in depression.

Dissecting the lateral hypothalamic input to the dorsal raphe nucleus and its role in major depression

Microglia activation is a critical component of the post-stroke inflammatory response; however, an accumulation of pro-inflammatory activated microglia can have a detrimental effect and lead to cognitive decline. Strokes that affect the basal ganglia can impair behavioural flexibility, an important component of executive function. An association between activated microglia in the white matter tracts and executive dysfunction has been established but not sufficiently evaluated in the context of stroke. Minocycline is a tetracycline derivative shown to effectively inhibit microglia activation. In this study, we used a rat model to investigate the effects of acute post-stroke minocycline treatment on cognitive outcomes and white matter pathology. Stroke was induced in 8-10-month-old male wildtype Fischer 344 rats by injection of endothelin-1 into the right dorsal striatum. Minocycline was administered for 4 days post-stroke prior to testing for behavioural flexibility, learning and memory using an operant conditioning-based set-shifting task and the Morris water maze. Brains were histologically examined at 28 days post-stroke to assess microglia activation, astrogliosis and infarct size. Results indicate a link between white matter activated microgliosis and behavioural outcomes post-stroke suggesting that modifying microglia activation post-stroke could protect the brain and improve cognitive outcomes.

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Atypical subiculum pyramidal neurons form dedicated projections and exhibit morphological and electrophysiological differences

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