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Growing evidence indicates that during early stages of Alzheimer&#39;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.

CAN-ACN 2021

Enhancing the potassium chloride co-transporter KCC2 reverses functional deficits associated with Alzheimer&#39;s disease-related mutations in mice

neurodegenaration

alzheimer disease

chloride

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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

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.

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/)

The 2021 Advocacy session, chaired and organized by CAN advocacy committee chair **Karun Singh**, will feature a special lecture and question period with Member of Parliament and past Science Minister **Kirsty Duncan**. This will be followed by a short overview of CAN’s advocacy activities over the last year. We invite you to participate in this session for insight from Dr. Duncan on the workings of Parliament Hill, and to learn more about what CAN has been doing to promote neuroscience research in Canada.

We are also excited to host **Lisa Willis** in the Equity Diversity and Inclusion session, organized by EDI committee chair **Jibran Khokhar**.

A special highlight of our meeting will be the lectures by award-winning young neuroscientists. We are please to host the CAN 2020 Young Investigator Award winner **Mihaela Iordanova**, and CAN 2021 Young Investigator Award winners **Aaron Phillips** and **Tabrez Siddiqui**. Highlights will also include presentation by the top three winners of the CAN-CIHR-INMHA Brain Star Award winners, **Claire Gizowski, Nuria Daviu Abant** and **Lukas Tamayo-Orrego**.

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Shernaz Bamji

President of the Canadian Association for Neuroscience

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Please head to https://can-acn.org/meeting-2021/registration-2021/ to register. 

14th Canadian Neuroscience Meeting from August 23rd-25th

Throughout life, the retina undergoes chemical and structural changes that ultimately result in altered functional properties. Electrophysiological testing is an objective method to functionally assess the state of the neuroretina. By using appropriate visual stimuli in the light-adapted eye, it is possible to isolate the contributions of specific cellular components to the elicited electrical response. In this study, we performed a light-adapted (30 cd m² background) flicker electroretinogram (ERG) in 36 adult vervet monkeys aged 9 to 28 years old, with no obvious signs of ocular pathology. A standard intensity light flash (2.57 cd s m²) was applied at eight different frequencies, ranging from 5 to 40 Hz. Changes in the stimulus-response characteristics were found in older individuals (21-28 years-old, N=16), when compared with recordings from younger monkeys (9-20 years-old, N=20). Specifically, a significant reduction in the averaged amplitude together with a prolonged implicit time of the b-wave was observed in older monkeys across all stimulus frequencies tested (p<0.05). Altogether, our findings corroborate the existent human literature, where ageing detrimentally affects photopic retinal responses. These results also highlight the potential use of non-human primates as a reliable model to study the early stages of visual processing over the lifespan. Overall, these age-dependent voltage and temporal changes might reflect ongoing pathological processes targeting the cone-bipolar subsystem.

Age-related changes in retinal function in the vervet monkey

Parvalbumin (PV)-GABAergic interneurons constitute the majority of interneurons in the cortex and play a key role in the function and synchronization of cortical networks. Alterations in PV-interneuron connectivity, in the medial prefrontal cortex (mPFC), have been related to psychiatric disorders. We have previously shown that the expression of the p75 neurotrophin receptor (p75NTR) regulates the time course of PV cell synapse maturation in a cell-autonomous fashion. Here, we study how p75NTR removal in postnatal PV cells affects the connectivity of PV interneurons and mPFC function in adult PV_Cre;p75NTRlox/lox mice. One important indication of PV cell maturation is the appearance of specialized extracellular matrix structures called perineural nets (PNNs) around the soma and primary dendrites of mature cortical PV cells. Conditional postnatal deletion of p75NTR in PV cells resulted in an increased perineural net (PNN) density and intensity around these cells, along with higher excitatory afferent and inhibitory efferent connectivity in PFC. These mice also showed deficits in attentional set-shifting task, a measure of attention and cognitive flexibility in mPFC, and in extinction of fear memories, both of which rely on mPFC function. Finally, we investigate whether the overexpression of P75NTR in mPFC of adult cKO can rescue PV cell structural deficit. Using a Cre-dependent adeno-associated virus, we observed a significant decrease in PV cell inhibitory efferent connectivity. Analysis on the PNN density and intensity around PV cell somata is currently ongoing. These findings uncover P75NTR as a critical regulator of PV circuit refinement and plasticity in adult PFC by simultaneously controlling PV cellular connectivity underlying cognitive function.

Role of p75 neurotrophin receptor in cortical parvalbumin-positive GABAergic interneurons and cognitive flexibility 

Topographic organization is commonly found in the sensory systems of vertebrates. Functional topographic maps are believed to follow a developmental progression from initially coarse to more precise through an activity-dependent refinement process. To examine the emergence of topographic organization in the retinotectal system, we performed longitudinal visual receptive field mapping by calcium imaging in the optic tectum of GCaMP6-expressing transgenic Xenopus laevis tadpoles. At stage 42, just one day after retinal axons arrive in the optic tectum, and the earliest time point when visually evoked responses could be detected, a crude retinotopic functional map was evident. Animals were imaged over the following week at stage 45 and stage 48, during which more precise retinotopic organization was observed. Next, by microinjecting GCaMP6s mRNA into one blastomere of two-cell stage embryos, we acquired bilateral mosaic tadpoles with GCaMP6s expression in postsynaptic tectal neurons on one side of the animal and in RGC axons crossing over to the tectum on the opposite side. This allowed independent observation of retinotopic maps in the pre- and post-synaptic elements in the tectum. To examine the contribution of N-methyl-D-aspartate (NMDA) receptors to map refinement, we reared tadpoles in the NMDA receptor antagonist MK-801. MK-801-rearing did not prevent the emergence of retinotopic maps, but produced changes in overall map organization compared to untreated animals, including more discontinuous topographic gradients and altered receptive field characteristics. These results provide evidence that NMDA receptor activity is dispensable for coarse topographic ordering of retinotectal inputs, but play a part in the fine-scale refinement of the retinotectal projection.

Topographic map formation and the effects of NMDA receptor blockade in the developing Xenopus retinotectal system

The formation and remodeling of synaptic contacts require the precise distribution and trafficking of proteins to specialized compartments. This dynamic trafficking of synaptic proteins is partly controlled by S-palmitoylation, which is the most common form of post-translational lipid modification in the brain. Notably, several studies have shown that synaptic proteins can be differentially palmitoylated in response to synaptic activity. However, it is unclear how changes in synaptic activity alters protein palmitoylation. Here we show that increasing synaptic activity in primary rat hippocampal cultures using a well-established chemical LTP (cLTP) paradigm leads to post-translational modifications in ZDHHC enzymes which in turn impact enzyme stability, protein interaction and function. Notably, we observe the same post-translational modifications following the acquisition of contextual fear memory in vivo. In contrast to that observed for palmitoylating enzymes, we observed no activity-induced changes in the activity of thioesterases nor post-translational modifications of the thioesterase, ABHD17. These findings suggest that the differential palmitoylation of synaptic proteins following synaptic stimulation is mediated through post-translational modifications of ZDHHC enzymes that in turn regulate enzyme stability and function, and not through changes in depalmitoylating thioesterases.

Dynamic regulation of palmitoyltransferases by synaptic activity

Mammalian spinal cord injury (SCI) occurs by a primary mechanical trauma that is exacerbated by a secondary cellular insult in the form of neuroinflammation, cell death, and reactive gliosis. The lack of functional recovery may be attributed to the inability of mammals to replace lost neurons. In zebrafish (Danio rerio), the secondary insult is attenuated and allows for the development of a spinal microenvironment that fosters regeneration. Radial glia lining the zebrafish central canal undergo injury-induced proliferation and neuronal differentiation, yet the molecular mechanisms that underlie these processes remain elusive. Previous reports have identified roles for purinergic P2Y2 and P2X7 receptors in mammalian neural progenitor cell proliferation and neuronal differentiation, respectively. Given that the purinergic system is evolutionarily conserved among vertebrates, we hypothesize that radial glia proliferation and neurogenesis following zebrafish SCI may be mediated by P2X7 and P2Y2 signaling. Preliminary immunohistochemical data suggests that radial glia express P2X7 and P2Y2 receptors. Preliminary Western blotting data shows significant upregulation of P2Y2 receptor expression at 1 day following zebrafish SCI, as well as significant downregulation of P2X7 receptor expression at 7 days. This contrasts the more gradual increase in P2Y2 receptor expression as well as the general increase in P2X7 receptor expression following mammalian SCI. Specific blockers for P2X7 and P2Y2 will be used to ascertain the roles of these receptors in the zebrafish SCI response. This work is well suited to advance our current understanding of successful central nervous system regeneration and elucidate the signaling pathways involved.

Adaptive purinergic P2X7 and P2Y2 signaling following spinal cord injury in Danio rerio

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.

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Age-related changes in retinal function in the vervet monkey

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