Biology subjects

Lacaille, J.-C.

Publications and source records attributed to Lacaille, J.-C..

9 recordsLinked to original sources

bioRxiv2025

Distinct subtypes of astrocytes selectively regulate specific inhibitory synapses

Astrocyte functional heterogeneity within a given neuronal circuit remains largely undetermined, particularly their role at tripartite synapses. Here, we examine multiple functional characteristics of astrocytes distinguished by their specific spatial relation to inhibitory synapses made on distinct hippocampal CA1 pyramidal cell domains: astrocytes covering the peri-somatic area in stratum pyramidale (SP) receiving input from Parvalbumin interneurons, or the apical dendritic area in stratum radiatum (SR) innervated by inhibitory inputs from Somatostatin interneurons. Whole-cell dye-filling and confocal imaging of SR astrocytes showed a typical bushy organization of processes while those of SP astrocytes were more polarized, indicating astrocyte morphological heterogeneity. In addition, SP astrocytes formed a smaller, yet polarised syncytium and displayed greater input resistance relative to SR astrocytes. The two populations of astrocyte are functionally different as indicated by their intrinsic Ca2+ signaling properties: SP astrocyte Ca2+ events had a lower frequency and temporal density, but greater amplitude, relative to SR astrocytes. Using the territorial segregation of inhibitory synapses, we observed that the selective activation using DREADD or blockade with intracellular BAPTA of the two populations of astrocytes regulated inhibitory synapses exclusively in their own syncytial territory. Furthermore, each astrocyte population selectively mediated long-term depression at the respective inhibitory synapses through Ca2+-dependent modulation of post-synaptic targets. These results indicate domain-specific regulation of inhibitory synapses by distinct SP and SR astrocyte syncytia. Transcriptional analysis revealed enriched gene expression in SP relative to SR astrocytes, notably for regulation of cell growth and morphology, synaptic function and signaling. Overall, our findings reveal a functional specialization of astrocyte subtypes in the hippocampus, highlighting heterogeneous astrocyte regulation of hippocampal synaptic networks important for learning and memory. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/654545v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@16639c9org.highwire.dtl.DTLVardef@5bf548org.highwire.dtl.DTLVardef@1448292org.highwire.dtl.DTLVardef@d86c00_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Genetic reduction of the translational repressors FMRP and 4E-BP2 preserves memory in mouse models of Alzheimer's disease

Alzheimers disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-{beta} oligomers (A{beta}Os) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.

neuroscience↗

bioRxiv2023

Stimulation of mRNA translation rescues hippocampal synaptic plasticity and memory in mouse models of Alzheimer's disease

Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimers disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that systemic treatment with (2R,6R)- hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AD-linked amyloid-{beta} oligomers (A{beta}Os) in mice. HNK activated hippocampal extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. Stimulation of S6 phosphorylation by HNK was mTORC1-dependent, while rescue of hippocampal LTP and memory in HNK-treated A{beta}O-infused mice was ERK1/2-dependent and, partially, mTORC1- dependent. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. Transcriptomic analysis further showed that HNK rescued signaling pathways that are aberrant in APP/PS1 mice, including inflammatory and hormonal responses, and programmed cell death. Taken together, our findings demonstrate that HNK induces signaling and transcriptional responses that correct deficits in hippocampal synaptic plasticity and memory in AD mouse models. These results raise the prospect that HNK could serve as a therapeutic to prevent or reverse memory decline in AD.

neuroscience↗

bioRxiv2023

Excitatory neuron-specific suppression of the integrated stress response pathway contributes to autism-related phenotypes in a mouse model of fragile X syndrome

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2 phosphorylation (p-eIF2), is suppressed in excitatory but not inhibitory neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2 is mediated via activation of the mTORC1. Genetic reduction of p-eIF2 only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, genetic restoration of p-eIF2 solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis and core phenotypes reminiscent of autism in a mouse model of FXS.

neuroscience↗

bioRxiv2023

mTORC1-mediated acquisition of reward-related spatial representations by hippocampal somatostatin interneurons

Plasticity of principal cells and inhibitory interneurons underlies hippocampal memory. Bidirectional modulation of somatostatin cell mTORC1 activity, a crucial translational control mechanism in synaptic plasticity, causes parallel changes in hippocampal CA1 somatostatin interneuron (SOM-IN) long-term potentiation and hippocampus-dependent memory, indicating a key role in learning. However, SOM-IN activity changes and behavioral correlates during learning, and the role of mTORC1 in these processes, remain ill-defined. To address these questions, we used two-photon Ca2+ imaging from SOM-INs during a virtual reality goal-directed spatial memory task in head-fixed control mice (SOM-IRES-Cre mice) or in mice with conditional knockout of Rptor (SOM-Rptor-KO mice) to block mTORC1 activity in SOM-INs. We found that control mice learn the task, but SOM-Raptor-KO mice exhibit a deficit. Also, SOM-IN Ca2+ activity became increasingly related to reward localization during learning in control mice but not in SOM-Rptor-KO mice. Four types of SOM-IN activity patterns related to reward location were observed, "reward off sustained", "reward off transient", "reward on sustained" and "reward on transient", and these responses showed global remapping after reward relocation in control but not SOM-Rptor-KO mice. Thus, SOM-INs develop mTORC1-dependent spatial coding related to learning reward localization. This coding may bi-directionally interact with pyramidal cells and other structures to represent and consolidate reward location.

neuroscience↗

bioRxiv2023

Both GEF domains of the autism and epilepsy-associated Trio protein are required for proper tangential migration of GABAergic interneurons

Recessive mutations in the TRIO gene are associated with intellectual deficiency (ID), autism spectrum disorder (ASD) and developmental epileptic encephalopathies (DEE). TRIO is a dual guanine nucleotide exchange factor (GEF) that activates Rac1, Cdc42 and RhoA. Trio has been extensively studied in excitatory neurons, and has recently been found to regulate the switch from tangential to radial migration in GABAergic interneurons (INs), through GEFD1-Rac1-dependent SDF1/CXCR4 signalling. Given the central role of Rho-GTPases during neuronal migration and the implication of IN pathologies in ASD and DEE, we investigated the relative roles of both Trios GEF domains in regulating the dynamics of INs tangential migration. In Trio-/- mice, we observed reduced numbers of tangentially migrating INs, with intact progenitor proliferation. Further, we noted increased growth cone collapse in developing INs, suggesting altered cytoskeleton dynamics. To bypass the embryonic mortality of Trio-/- mice, we generated Dlx5/6Cre;Trioc/c conditional mutant mice, which develop spontaneous seizures and behavioral deficits reminiscent of ASD and ID. These phenotypes are associated with reduced cortical IN density and functional cortical inhibition. Mechanistically, this reduction of cortical IN numbers reflects a premature switch to radial migration, with an aberrant early entry in the cortical plate, as well as major deficits in cytoskeletal dynamics, including enhanced leading neurite branching and slower nucleokinesis reflecting reduced actin filament condensation and turnover. Further, we show that both Trio GEFD1 and GEFD2 domains are required for proper IN migration, with a dominant role of the RhoA-activating GEFD2 domain. Altogether, our data show a critical role of the DEE/ASD-associated Trio gene in the establishment of cortical inhibition and the requirement of both GEF domains in regulating IN migration dynamics.

neuroscience↗

bioRxiv2021

Long-term potentiation at pyramidal cell to somatostatin interneuron synapses controls hippocampal network plasticity and memory

Hippocampal somatostatin (SOM) cells are dendrite-projecting inhibitory interneurons. CA1 SOM cells receive major excitatory inputs from pyramidal cells (PC-SOM synapses) which show mGluR1a- and mTORC1-mediated long-term potentiation (LTP). PC-SOM synapse LTP contributes to CA1 network metaplasticity and memory consolidation, but whether it is sufficient to regulate these processes remains unknown. Here we used optogenetic stimulation of CA1 pyramidal cells and whole cell recordings in slices to show that optogenetic theta burst stimulation (TBSopto) produces LTP at PC-SOM synapses. At the network level, we found that TBSopto differentially regulates metaplasticity of pyramidal cell inputs: enhancing LTP at Schaffer collateral synapses and depressing LTP at temporo-ammonic synapses. At the behavioral level, we uncovered that in vivo TBSopto regulates learning-induced LTP at PC-SOM synapses, as well as contextual fear memory. Thus, LTP of PC-SOM synapses is a long-term feedback mechanism controlling pyramidal cell synaptic plasticity, sufficient to regulate memory consolidation.

neuroscience↗

bioRxiv2020

Early defects in lysosomal storage diseases disrupt excitatory synaptic transmission

At least two thirds of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPS IIIC, Sanfilippo disease type C) caused by mutations in the HGSNAT gene and lysosomal storage of heparan sulfate the major burden is progressive and severe neuropsychiatric problems, mental retardation, and dementia though to be mainly mediated by neurodegeneration. HGSNAT knockout mice match human clinical phenotype and develop hyperactivity followed by memory impairment and death. In order to understand whether early clinical symptoms in MPS IIIC mice occurring before the onset of massive neurodegeneration are caused by neuronal dysfunction we studied synaptic transmission and morphology in cultured hippocampal and CA1 pyramidal neurons of MPSIIIC mice. Synaptic spines were also studied in other mouse LSD models and postsynaptic densities in post-mortem cortices of human neurological MPS patients. Cultured hippocampal and CA1 pyramidal neurons of MPS IIIC mice showed a drastic decrease or abnormal distribution of multiple pre- and postsynaptic proteins that could be rescued in vitro and in vivo by virus-mediated gene correction. Dendritic spine densities were immature in cultured hippocampal MPS IIIC mouse neurons and reduced in pyramidal neurons of mouse models of MPS IIIC and other (Tay-Sachs, sialidosis) LSD starting from postnatal day 10. MPS IIIC neurons presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganised microtubule network and partially impaired axonal transport of synaptic proteins. Postsynaptic densities were also reduced in post-mortem cotrees of human MPS I, II, IIIA, C and D patients suggesting that the pathology is common for these neurological LSD. Together, our results demonstrate that lysosomal storage causes alterations in synaptic structure and abnormalities in neurotransmission originating from disrupted vesicular transport and preceding the first cognitive symptoms and suggest drugs known to affect synaptic transmission can be potentially applied to treat behavioral and cognitive defects in neurological LSD patients.

neuroscience↗

bioRxiv2019

Regulation of hippocampal memory by mTORC1 in somatostatin interneuron

Translational control of long-term synaptic plasticity via Mechanistic Target Of Rapamycin Complex 1 (mTORC1) is crucial for hippocampal learning and memory. The role of mTORC1 is well-characterized in excitatory principal cells but remains largely unaddressed in inhibitory interneurons. Here we used cell type-specific conditional knockout strategies to alter mTORC1 function selectively in somatostatin (SOM) inhibitory interneurons (SOM-INs). We found that up- and down-regulation of SOM-IN mTORC1 activity bi-directionally regulates contextual fear and spatial memory consolidation. Moreover, contextual fear learning induced a metabotropic glutamate receptor type 1 (mGluR1) mediated long-term potentiation (LTP) of excitatory input synapses onto hippocampal SOM-INs, that was dependent on mTORC1. Finally, the induction protocol for mTORC1-mediated late-LTP in SOM-INs regulated Schaffer collateral pathway LTP in pyramidal neurons. Thus, mTORC1 activity in somatostatin interneurons contributes to learning-induced persistent plasticity of their excitatory synaptic inputs and hippocampal memory consolidation, uncovering a role of mTORC1 in inhibitory circuits for memory.

neuroscience↗