Bognár A, Nejad GG, Rens G
… +2 more, Raman R, Vogels R
Prog Neurobiol
· 2025 Jun · PMID 40254177
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The primate Superior Temporal Sulcus (STS) plays a pivotal role in the recognition of bodies and their actions, which is essential for survival and social interaction with conspecifics. Here, we show that, surprisingly,...The primate Superior Temporal Sulcus (STS) plays a pivotal role in the recognition of bodies and their actions, which is essential for survival and social interaction with conspecifics. Here, we show that, surprisingly, a sizable proportion of macaque middle ventral STS units are selective for static bodies and random dot motion. They show a faithful representation of random dot motion direction, with motion directions differing by 180 degrees being represented distinctly, although responding more strongly to complex optic flow patterns. This aligns with an fMRI experiment in which we show that the mid-STS body patch, defined by a greater activation to static bodies compared to faces and objects, is also more strongly activated by moving random dot patterns compared to static ones, especially when including complex optic flow patterns. More anterior ventral STS body-selective units demonstrate a less pronounced random dot motion selectivity and this is mainly for complex optic flow patterns. Moreover, middle STS units, but rarely those of the anterior STS, respond selectively to dynamic dot patterns in which body parts are visible solely through motion, and their preference correlates with those for videos of acting monkeys. Overall, these findings highlight an association between body and motion processing in the macaque ventral STS, which might result from the co-occurrence of body features and motion during the observation of bodily actions.
Autism spectrum disorders (ASDs) comprise a broad category of neurodevelopmental disorders that include repetitive behaviors and difficulties in social interactions. Notably, individuals with ASDs exhibit significant imp...Autism spectrum disorders (ASDs) comprise a broad category of neurodevelopmental disorders that include repetitive behaviors and difficulties in social interactions. Notably, individuals with ASDs exhibit significant impairments in motor skills even prior to the manifestation of other core symptoms. These skills are crucial for daily activities, such as communication, imitation, and exploration, and hold significant importance for individuals with ASDs. This review seeks to offer new insights into the understanding of motor skill impairments by delineating the pathological mechanisms underlying motor skill learning impairments associated with gene mutations in Fmr1, Chd8, Shank3, BTBR, 16p11.2, and Mecp2, predominantly drawing from well-characterized genetic mouse model studies and proposing potential targets for future therapeutic interventions. We further discuss the underlying pathogenic abnormalities associated with the development of specific brain regions within the cerebellum and cerebrum, as well as disruptions in the structure and function of critical neuronal connectivity pathways. Additional research utilizing epidemiological data, clinical observations, and animal research methodologies is warranted to enhance our understanding of the effect of motor skill learning on the growth, development, and social integration of children. Ultimately, our review suggests potential targets for future therapeutic interventions.
Stress granules (SGs) are membrane-less cytoplasmic structures formed by cells in response to external stress, primarily composed of mRNA and proteins. The dynamic properties of their assembly, maintenance, and disassemb...Stress granules (SGs) are membrane-less cytoplasmic structures formed by cells in response to external stress, primarily composed of mRNA and proteins. The dynamic properties of their assembly, maintenance, and disassembly play crucial roles in cellular homeostasis. Recent studies have increasingly revealed that aberrations in SGs dynamics are closely related to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review summarizes the latest research progress on SGs dynamics in neurodegenerative diseases. It begins with an overview of the basic biological characteristics of SGs and their functions in neurons, followed by an in-depth exploration of the mechanisms and regulatory pathways of SGs dynamics. The review then summarizes potential therapeutic strategies targeting SGs dynamics abnormalities, particularly through small molecule drugs to modulate SGs formation and disassembly, aiming to delay or halt the progression of neurodegenerative diseases. The review also highlights the application prospects of these interventions in treating neurodegenerative diseases. Finally, the review introduces current techniques used to study SGs dynamics, discussing their advantages, limitations, and future development possibilities. This review aims to provide researchers with a comprehensive perspective to advance the understanding and clinical application of SGs dynamics in the field of neurodegenerative diseases.
Barbour MA, Whitehead B, Gumbo C
… +2 more, Karelina K, Weil ZM
Prog Neurobiol
· 2025 May · PMID 40113130
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Traumatic brain injuries (TBI) significantly increase the risk of both ischemic and hemorrhagic strokes, with effects persisting for years after the initial injury. The mechanisms underlying this increased stroke risk ar...Traumatic brain injuries (TBI) significantly increase the risk of both ischemic and hemorrhagic strokes, with effects persisting for years after the initial injury. The mechanisms underlying this increased stroke risk are complex, multifactorial, and incompletely understood but likely include chronic cerebrovascular dysfunction, blood-brain barrier disruption, and inflammatory responses. Epidemiological studies consistently show that TBI is an independent risk factor for stroke, with more severe injuries associated with greater risk, especially for hemorrhagic strokes. Traditional risk factors for stroke, such as hypertension, poor diet, and sedentary lifestyle, further elevate the risk in TBI survivors. Modifiable lifestyle factors, such as improving sleep, increasing physical activity, and adopting heart-healthy diets, offer potential intervention points to mitigate stroke risk. Pharmacological considerations, including the use of antidepressants, anticoagulants, and statins, also influence stroke risk, particularly with regard to hemorrhagic complications. This review explores the pathophysiological mechanisms linking TBI and stroke, emphasizing the need for future research to identify specific biomarkers and imaging techniques to predict stroke vulnerability in TBI patients. Addressing the gaps in understanding, particularly regarding small vessel pathology, will be essential to developing targeted therapies for reducing stroke incidence in TBI survivors.
Prog Neurobiol
· 2025 Jun · PMID 40107380
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INTRODUCTION: The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mo...INTRODUCTION: The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success. METHODS: We tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI. RESULTS: Although network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best. DISCUSSION: This mathematical exposition of the "pas de deux" of co-evolving proteins provides quantitative, whole-brain support to the concept of amyloid-facilitated-tauopathy rather than the classic amyloid-cascade or pure-tau hypotheses, and helps explain certain known but poorly understood aspects of AD.
Langlais VC, Mountadem S, Benazzouz I
… +15 more, Amadio A, Matos M, Jourdes A, Cannich A, Julio-Kalajzic F, Belluomo I, Matias I, Maitre M, Lesté-Lasserre T, Marais S, Avignone E, Marsicano G, Bellocchio L, Oliet SHR, Panatier A
The activation of classical NMDA receptors (NMDARs) requires the binding of a co-agonist in addition to glutamate. Whereas astrocytic-derived d-serine was shown to play such a role at CA3-CA1 hippocampal synapses, the ex...The activation of classical NMDA receptors (NMDARs) requires the binding of a co-agonist in addition to glutamate. Whereas astrocytic-derived d-serine was shown to play such a role at CA3-CA1 hippocampal synapses, the exact mechanism by which neurons interact with neighboring astrocytes to regulate synaptic d-serine availability remains to be fully elucidated. Considering the close anatomical apposition of astrocytic and neuronal elements at synapses, the aforementioned process is likely to involve cells adhesion molecules. One very likely candidate could be the astrocytic EphB3 receptor and its neuronal partner, ephrinB3. Here, we first showed in acute hippocampal slices from adult mice that stimulation of EphB3 receptors with exogenous ephrinB3 increased d-serine availability at CA3-CA1 synapses, resulting in an increased NMDAR activity. Conversely, inhibiting endogenous EphB3 receptors caused an impairment of both synaptic NMDAR activity and NMDAR-dependent long-term synaptic potentiation (LTP), effects that could be rescued by exogenous d-serine. Most interestingly, knocking down EphB3 receptors specifically in astrocytes yielded a similar impairment in hippocampal plasticity and, most importantly, caused a deficit in novel object recognition memory. Altogether, our data thus indicate that EphB3 receptors in hippocampal astrocytes play a key role in regulating synaptic NMDAR function, activity-dependent plasticity and memory.
Classically, the insula is considered an associative multisensory cortex where emotional awareness emerges through the integration of interoceptive and exteroceptive information, along with autonomic regulation. However,...Classically, the insula is considered an associative multisensory cortex where emotional awareness emerges through the integration of interoceptive and exteroceptive information, along with autonomic regulation. However, since early intracortical microstimulation (ICMS) studies, the insular cortex has also been conceived as a mosaic of anatomo-functional sectors processing various types of sensory information to generate specific overt behaviors. Based on this, the insula has been subdivided into distinct functional fields: an anterior field associated with oroalimentary behaviors, a middle field involved dorsally in hand movements and ventrally in emotional reactions, and a posterior field engaged in axial and proximal movements. Nevertheless, the anatomo-functional networks through which these fields produce motor behaviors remain largely unknown. To fill this gap in the present study, we investigated the connectivity of the macaque insula using a multimodal approach which combines resting-state fMRI with data from tract-tracing injections in insular functional fields defined by ICMS, as well as in brain areas known to be connected to the insula and characterized by specific somatotopic organization. The results revealed that each insular functional field takes part in distinct somatotopically organized network modulating specific motor or visceromotor behaviors, extending previous models that subdivide the insula primarily based on the types of interoceptive and exteroceptive information it receives. Our findings posit the various insular sectors as interfaces that synthesize diverse interoceptive and exteroceptive inputs into coherent subjective experiences and decision-making processes, within an embodied and enactive framework, that moves beyond the traditional dichotomy between sensory experience and motor behavior.
Puangmalai N, Aday AE, Samples M
… +12 more, Bhatt N, Cascio FL, Marcatti M, Park SJ, Fung L, Jerez C, Penalva LO, Zhao Y, Hao H, Lugano D, Kayed R, Montalbano M
Prog Neurobiol
· 2025 Apr · PMID 40064283
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Alzheimer's disease (AD) is marked by cytoplasmic proteinopathies, primarily involving misfolded Tau protein. Pathogenic Tau species, such as soluble oligomers and fibrils, disrupt RNA metabolism, though the mechanisms a...Alzheimer's disease (AD) is marked by cytoplasmic proteinopathies, primarily involving misfolded Tau protein. Pathogenic Tau species, such as soluble oligomers and fibrils, disrupt RNA metabolism, though the mechanisms are unclear. Recent research indicates that RNA has a crucial role in Tau aggregation. Our study builds on this by noting significant co-deposition of RNA-Binding Proteins (RBPs) with Tau in AD and Frontotemporal dementia (FTLD) brains. Using molecular and cellular techniques, we investigate the interaction between RNA dynamics and Tau aggregation, focusing on the localization and aggregation of Tau and RBPs, particularly Musashi (MSI), within neuronal nuclei. Through cyto-fluorometric, biochemical, and cellular assays, we reveal the importance of Tau/RBP interplay in primary cortical neurons expressing wild-type and mutant Tau. Pathogenic Tau oligomers alter MSI protein localization and function, causing cytoplasmic and nuclear aggregation. Mass spectrometry of the MSI1 nuclear interactome in Tau models shows disrupted RNA metabolism pathways, including ribosomal biogenesis, RNA splicing, and protein folding. Moreover, RNA immunoprecipitation assay revealed a remarkable impact of mutant P301L Tau on MSI1 ability to bind RNA targets. These findings highlight potential targets for early neurodegenerative therapeutic interventions.
Excessive neural activity in the medial temporal lobe commonly associates with cognitive decline in elderly humans and also in rodents.An attractive model pathway to study synaptic mechanisms underlying age-dependent cir...Excessive neural activity in the medial temporal lobe commonly associates with cognitive decline in elderly humans and also in rodents.An attractive model pathway to study synaptic mechanisms underlying age-dependent circuit hyperexcitability is the connection made by lateral entorhinal cortex cells onto the dentate gyrus (LEC→DG). Both structures are particularly affected by age and, importantly, in behaviorally characterized aged rats, learning impairment correlates with diminished feedforward inhibition of granule cells recruited by LEC inputs. In this rat model of aging, we evaluated how overexpression of Neuronal Pentraxin 2 (NPTX2) in the LEC, essential for stabilizing excitatory inputs onto fast-spiking inhibitory interneurons (FS-INs), enhances feedforward inhibition and improves spatial memory in impaired individuals. In addition, we found that FS-INs from unimpaired aged individuals have an increased excitatory drive compared to young individuals. These findings support the notion that NPTX2-mediated compensatory mechanisms to enhance the recruitment of FS-INs are crucial to maintaining proficient memory performance during aging.
Sleep disorders can increase amyloid beta (Aβ) burden in the brain and are linked to Alzheimer's disease (AD) risk. The precise mechanism by which sleep disturbances elevate Aβ levels is unclear. Our previous study has d...Sleep disorders can increase amyloid beta (Aβ) burden in the brain and are linked to Alzheimer's disease (AD) risk. The precise mechanism by which sleep disturbances elevate Aβ levels is unclear. Our previous study has demonstrated that knocking down encoding gene Grin2a of astrocytic N-methyl-D-aspartate (NMDA) receptors GluN2A subunit could aggravate sleep deprivation (SD)-induced elevation of Aβ, indicating a protective role of astrocytic GluN2A in SD; but the underlying mechanism needs to be further elucidated. In our present study, using rat models of SD combined with specific astrocytic Grin2a knockdown or overexpression in the hippocampus, and a cell model of primary cultured hippocampal astrocytes, we reveal a novel mechanism that astrocytic GluN2A alleviates SD-induced increases in Aβ. We demonstrated that astrocytic GluN2A mainly affected Aβ degradation and clearance through regulating degradation enzyme neprilysin and Aquaporin-4 (AQP4), via the calcineurin/NFAT pathway. Our study provides supportive evidence for the novel role and mechanism of astrocytic GluN2A in Aβ elimination, which would contribute to the discovery of new therapeutic strategies for Aβ-related diseases such as AD.
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Most current treatments for TBI and other neurological disorders focus on the brain, often overlooking the significant contributions of per...Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Most current treatments for TBI and other neurological disorders focus on the brain, often overlooking the significant contributions of peripheral organs to disease progression. Emerging evidence suggests that organs such as the liver and adipose tissue play crucial roles in TBI pathogenesis. The liver synthesizes lipids and proteins vital for brain function, while adipose tissue provides hormones and metabolites that influence brain activity. New research indicates that the liver and adipose tissue work in concert with the hypothalamus to regulate essential processes, such as body temperature, which become disrupted in TBI. Additionally, the brain-peripheral axis-a complex network of visceral nerve pathways, hormones, and metabolites-plays a bidirectional role in regulating brain plasticity and function. Understanding how TBI leads to dysregulation of the liver, adipose tissue, and other organs could unlock new therapeutic opportunities for treating TBI and related neurological disorders. The intricate autonomic network involving hypothalamic and enteric neurons, along with visceral nerve pathways and hormones, presents both pathological targets and therapeutic potential. We examine scientific evidence suggesting that correcting disturbances in systemic physiology could enhance the brain's capacity for healing. However, the interdependence of this autonomic network implies that treating dysfunction in one area may affect others. Therefore, we also explore the mechanisms by which diet and exercise can comprehensively impact the brain-peripheral axis, supporting the healing process. CHEMICAL COMPOUNDS: D-Fructose (PubChem CID 2723872); docosahexaenoic acid (PubChem CID 45934466); eicosapentaenoic acid (PubChem 5282847).
Amyloid proteins have long been in the spotlight for being involved in many degenerative diseases including Alzheimer´s, Parkinson´s or type 2 diabetes, which currently cannot be prevented and for which there is no effec...Amyloid proteins have long been in the spotlight for being involved in many degenerative diseases including Alzheimer´s, Parkinson´s or type 2 diabetes, which currently cannot be prevented and for which there is no effective treatment or cure. Here we provide a comprehensive review of inhibitors that act directly on the amyloidogenic pathway (at the monomer, oligomer or fibril level) of key pathological amyloids, focusing on the most representative amyloid-related diseases. We discuss the latest advances in preclinical and clinical trials, focusing on cutting-edge developments, particularly on nanomaterials-based inhibitors, which offer unprecedented opportunities to address the complexity of protein misfolding disorders and are revolutionizing the landscape of anti-amyloid therapeutics. Notably, nanomaterials are impacting critical areas such as bioavailability, penetrability and functionality of compounds currently used in biomedicine, paving the way for more specific therapeutic solutions tailored to various amyloid-related diseases. Finally, we highlight the window of opportunity opened by comparative analysis with so-called functional amyloids for the development of innovative therapeutic approaches for these devastating diseases.
Surround modulation is a fundamental property of V1 neurons, playing critical roles in stimulus integration and segregation. It is believed to be orientation-specific, as neurons' responses at preferred orientations are...Surround modulation is a fundamental property of V1 neurons, playing critical roles in stimulus integration and segregation. It is believed to be orientation-specific, as neurons' responses at preferred orientations are suppressed more by iso-oriented surrounds than by cross-oriented surrounds. Here, we investigated an alternative hypothesis that surround modulation is primarily orientation-unspecific, in that the observed "orientation-specific" surround effects actually reflect overall gain changes that affect neurons tuned to all orientations. We employed two-photon calcium imaging to compare V1 population orientation tuning functions under iso- and cross-surround modulation in awake, fixating macaques. While confirming "orientation-specific" surround suppression in individual neurons, our analysis of the population orientation tuning functions revealed that iso-surrounds induce a general orientation-unspecific suppression across all orientation-tuned neurons, plus weak orientation-specific suppression to neurons tuned to the center stimulus orientation. Furthermore, cross-surrounds mainly reduce orientation-unspecific suppression by scaling up responses of all orientation-tuned neurons. These findings suggest a model of population gain control where surround stimuli mostly scale the responses of the neuronal population. Further population coding analyses supported this conclusion, demonstrating that surround suppression leads to degraded target orientation information at least partially due to a reduced number of contributing neurons with diverse orientation preferences.
Reactivation refers to the re-emergence of activity in neuronal ensembles that were active during information encoding. Hippocampal CA1 neuronal ensembles generate firing activities that encode the temporal association a...Reactivation refers to the re-emergence of activity in neuronal ensembles that were active during information encoding. Hippocampal CA1 neuronal ensembles generate firing activities that encode the temporal association among time-separated events. However, whether and how temporal association memory-related CA1 neuronal ensembles reactivate during sleep and their role in temporal association memory consolidation remain unclear. We utilized multiple unit recordings to monitor CA1 neuronal activity in mice learning a trace eyeblink conditioning (tEBC) task, in which presentation of the conditioned stimulus (CS, a light flash) was paired with presentation of the unconditioned stimulus (US, corneal puff) by a time-separated interval. We found that the CS-US paired training mice exhibited few conditioned eyeblink responses (CRs) at the initial-learning stage (ILS) and an asymptotic level of CRs at the well-learning stage (WLS). More than one third of CA1 pyramidal cells (PYR) in the CS-US paired training mice manifested a CS-evoked firing activity that was sustained from the CS to time-separated interval. The CS-evoked PYR firing activity was required for the tEBC acquisition and was greater when the CRs occurred. Intriguingly, the CS-evoked firing PYR ensembles reactivated, which coincided with increased hippocampal ripples during post-training sleep. The reactivation of CS-evoked firing PYR ensembles diminished across learning stages, with greater strength in the ILS. Disrupting the ripple-associated PYR activity impaired both the reactivation of CS-evoked firing PYR ensembles and tEBC consolidation. Our findings highlight the features of hippocampal CA1 neuronal ensemble reactivation during sleep, which support the consolidation of temporal association memory.
Partial reprogramming induced by the controlled and cyclical overexpression of Yamanaka factors in the nervous system has so far succeeded in reversing some aging-associated phenotypes, such as improving memory function....Partial reprogramming induced by the controlled and cyclical overexpression of Yamanaka factors in the nervous system has so far succeeded in reversing some aging-associated phenotypes, such as improving memory function. These promising results suggest that partial reprogramming could be a potential strategy to prevent or mitigate aging-related pathologies like tauopathies, including Alzheimer's disease. Here, we explore the potential of this strategy in addressing tauopathy development in the P301S mouse model. To achieve this, a new transgenic animal was created that can inducibly overexpress Yamanaka factors upon doxycycline administration and carries the Tau-P301S mutation, which leads to tauopathy development. The results of this study show a significant improvement in key pathological features of tauopathies in the hippocampus, including reversed tauopathy, alleviated reactive astrogliosis, age-related reduction of the H3K9me3 epigenetic marker, along with improved spatial memory, which has been described as deteriorated in this model. These findings reinforce the potential of partial reprogramming as a therapeutic strategy to combat brain pathologies associated with aging.
Demyelinating disorders, characterizing by the loss of myelin integrity, present significant challenges due to their impact on neurological function and lack of effective treatments. Understanding the mechanisms underlyi...Demyelinating disorders, characterizing by the loss of myelin integrity, present significant challenges due to their impact on neurological function and lack of effective treatments. Understanding the mechanisms underlying myelin damage is crucial for developing therapeutic strategies. Triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal immune receptor predominantly found on microglial cells, plays essential roles in phagocytosis and lipid metabolism, vital processes in neuroinflammation and immune regulation. Emerging evidence indicates a close relationship between TREM2 and various aspects of myelin sheath dynamics, including maintenance, response to damage, and regeneration. This review provides a comprehensive discussion of TREM2's influence on myelin physiology and pathology, highlighting its therapeutic potential and putative mechanisms in the progression of demyelinating disorders.
Jie H, Petrus E, Pothayee N
… +1 more, Koretsky AP
Prog Neurobiol
· 2025 Apr · PMID 40010627
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Neuroplasticity in sensory brain areas supports adaptation after nerve injury and fundamentally impacts sensation and movement. However, limited neuroplasticity in somatosensory areas due to the early critical period mak...Neuroplasticity in sensory brain areas supports adaptation after nerve injury and fundamentally impacts sensation and movement. However, limited neuroplasticity in somatosensory areas due to the early critical period makes determining the role of thalamocortical (TC) inputs in sensorimotor signal processing challenging. Here, we demonstrated that reactivation of TC neuroplasticity was associated with an increase in the number of neurons in layer IV (L4) of the whisker primary somatosensory cortex (wS1) with a stable excitation-inhibition ratio. Highly synchronized neural activity in L4 propagated throughout the wS1 column and to the downstream areas, including whisker secondary somatosensory, primary motor cortices, and contralateral wS1. These results provide crucial evidence that TC inputs can alter the neural activity of sensory-motor pathways even after the critical period. Altogether, these enormous changes in sensorimotor circuit activity are important for adaptation following an injury such as limb loss, stroke, or other forms of neural injury.
Vestibular schwannoma (VS), characterized by the absence of merlin expression, is the most prevalent benign tumor located at the cerebellopontine angle, lacking approved pharmaceutical interventions except for off-label...Vestibular schwannoma (VS), characterized by the absence of merlin expression, is the most prevalent benign tumor located at the cerebellopontine angle, lacking approved pharmaceutical interventions except for off-label utilization of bevacizumab. The role of Tumor stiffness-Focal adhesion kinase (FAK) activation in fueling tumor progression is well-established, with merlin deficiency serving as a biomarker for tumor sensitivity to FAK inhibitors. In this context, we investigated whether Tumor stiffness-FAK contributes to VS progression. Single-cell RNA sequencing revealed associations between VS progression and gene sets related to "Response to mechanical stimulus" and "Neurotrophin signaling pathway". Histological studies indicated a potential involvement of neurotrophins in early stages of VS tumorigenesis, while enhanced Extracellular matrix (ECM) remodeling-Tumor stiffness-FAK signaling accompanies later stages of VS progression. In vitro experiments demonstrated that elevated matrix stiffness induces cytoskeletal remodeling, cell proliferation, and metalloproteinase expression in VS cells by activating FAK. Conversely, FAK inhibition diminishes these effects. Collectively, this study suggests that ECM remodeling-Tumor stiffness contributes to VS progression via FAK activation, positioning FAK as a promising therapeutic target in treating VS.
Thyroid hormone (TH) transporters such as the monocarboxylate transporter Mct8 and the organic anion transporting protein Oatp1c1 facilitate TH transport into target cells. In humans, inactivating mutations in MCT8 resul...Thyroid hormone (TH) transporters such as the monocarboxylate transporter Mct8 and the organic anion transporting protein Oatp1c1 facilitate TH transport into target cells. In humans, inactivating mutations in MCT8 result in Allan-Herndon-Dudley syndrome (AHDS), a severe psychomotor retardation with hallmarks of a central TH deficit and frequently observed seizures of unknown etiology. Here, we aimed to investigate seizure susceptibility in AHDS by using Mct8/Oatp1c1 double-knockout (Dko) mice, a well-established AHDS model. We tested seizure susceptibility using the pilocarpine model and observed a significantly faster occurrence of status epilepticus (SE) and more severe responses to seizure induction in Dko animals. We analyzed neuronal alterations in the hippocampus, an area central in seizure pathology, 12 h after SE by immuno-fluorescence and in situ hybridization (ISH). Dko mice presented increased cFos immunoreactivity, and ectopic expression of somatostatin in CA3 neurons. To unravel underlying mechanisms, we studied neurotransmitter systems in murine hippocampi during development at P12 and in adulthood. Employing immuno-fluorescence, ISH and qPCR analyses, we revealed an abnormal development of the inhibitory GABAergic, excitatory glutamatergic and cholinergic systems in Dko mice. Together, our data point to an altered inhibition/excitation balance in the Dko hippocampus that may explain the increased seizure susceptibility.
Depret N, Gleizes M, Moreau MM
… +13 more, Poirault-Chassac S, Quiedeville A, Carvalho SDS, Venugopal V, Abed ASA, Ezan J, Barthet G, Mulle C, Desmedt A, Marighetto A, Racca C, Montcouquiol M, Sans N
In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excresce...In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites of CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive "detonator" properties due to low initial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimer's disease. Here, we identify the core PCP gene Vangl2 as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working / everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions.