The brain faces the challenging task of preserving a consistent portrayal of the external world in the face of disruptive sensory inputs. What alterations occur in sensory representation amidst noise, and how does brain...The brain faces the challenging task of preserving a consistent portrayal of the external world in the face of disruptive sensory inputs. What alterations occur in sensory representation amidst noise, and how does brain activity adapt to it? Although it has previously been shown that background white noise (WN) decreases responses to salient sounds, a mechanistic understanding of the brain processes responsible for such changes is lacking. We investigated the effect of background WN on neuronal spiking activity, membrane potential, and network oscillations in the mouse central auditory system. We found that, in addition to increasing background spiking activity in the auditory cortex and thalamus, background WN decreases neural activity fluctuations, as reflected in the membrane potential of single neurons and the local field potential. Blocking acetylcholine signaling in the auditory cortex eliminated the WN-dependent increase in background activity as well as the shift in slow-wave oscillations. Together, our observations show that background WN is not filtered away along the auditory pathway, but rather drives sustained changes in cortical activity that can be reverted by blocking cholinergic inputs.
Ketamine administration during adolescence affects cognitive performance; however, its long-term impact on synaptic function and neuronal integration in the hippocampus a brain region critical for cognition remains uncle...Ketamine administration during adolescence affects cognitive performance; however, its long-term impact on synaptic function and neuronal integration in the hippocampus a brain region critical for cognition remains unclear. Using functional and molecular analyses, we found that chronic ketamine administration during adolescence exerts long-term effects on synaptic integration, expanding the temporal window in an input-specific manner affecting the inner molecular layer but not the medial perforant path inputs in the adult mouse dorsal hippocampal dentate gyrus. Ketamine also alters the excitatory/inhibitory balance by reducing the efficacy of inhibitory inputs likely due to a reduction in parvalbumin-positive interneurons number and function. These findings indicate that during adolescence, ketamine exerts a strong effect on inhibitory synaptic function mediated by parvalbumin-positive neurons that ultimately impact synaptic integration in the dorsal adult dentate gyrus, which could help to understand the neurobiological and functional bases that confer greater vulnerability to the adolescent brain.
Covelo J, Camassa A, Sanchez-Sanchez JM
… +14 more, Manasanch A, Porta LD, Cancino-Fuentes N, Barbero-Castillo A, Robles RM, Bosch M, Tapia-Gonzalez S, Merino-Serrais P, Carreño M, Conde-Blanco E, Arboix JR, Roldán P, DeFelipe J, Sanchez-Vives MV
Elucidating human cerebral cortex function is essential for understanding the physiological basis of both healthy and pathological brain states. We obtained extracellular local field potential recordings from slices of n...Elucidating human cerebral cortex function is essential for understanding the physiological basis of both healthy and pathological brain states. We obtained extracellular local field potential recordings from slices of neocortical tissue from refractory epilepsy patients. Multi-electrode recordings were combined with histological information, providing a two-dimensional spatiotemporal characterization of human cortical dynamics in control conditions and following modulation of the excitation/inhibition balance. Slices expressed spontaneous rhythmic activity consistent with slow wave activity, comprising alternating active (Up) and silent (Down) states (Up-duration: 0.08 ± 0.03 s, Down-duration: 2.62 ± 2.12 s, frequency: 0.75 ± 0.39 Hz). Up states propagated from deep to superficial layers, with faster propagation speeds than in other species (vertical: 64.6 mm/s; horizontal: 65.9 mm/s). GABA blockade progressively transformed the emergent activity into epileptiform discharges, marked by higher firing rates, faster network recruitment and propagation, and infraslow rhythmicity (0.01 Hz). This dynamical characterization broadens our understanding of the mechanistic organization of the human cortical network at the micro- and mesoscale.
It is well established that when we hold more content in working memory, we are slower to act upon part of that content when it becomes relevant for behavior. Here, we asked whether this load-related slowing is due to sl...It is well established that when we hold more content in working memory, we are slower to act upon part of that content when it becomes relevant for behavior. Here, we asked whether this load-related slowing is due to slower access to the sensory representations held in working memory (as predicted by serial working-memory search), or by a reduced preparedness to act upon those sensory representations once accessed. To address this, we designed a visual-motor working-memory task in which participants memorized the orientation of two or four colored bars, of which one was cued for reproduction. We independently tracked EEG markers associated with the selection of visual (cued item location) and motor (relevant manual action) information from the EEG time-frequency signal, and compared their latencies as a function of memory load. We confirm slower memory-guided behavior with higher working-memory load and show that this is associated with delayed motor selection. In contrast, we find no evidence for a concomitant delay in the latency of visual selection. Moreover, we show that variability in decision times within each memory-load condition is associated with corresponding changes in the latency of motor, but not visual selection. These results reveal how memory load affects our preparedness to act on sensory representations in working memory, while leaving sensory access itself unaffected. This posits action readiness as a key factor that shapes the speed of memory-guided behavior and that underlies delayed responding with higher working-memory load.
Koyano KW, Taubert J, Robison W
… +2 more, Waidmann EN, Leopold DA
Prog Neurobiol
· 2025 Feb · PMID 39755201
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The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact...The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact tuning properties remain unclear. For example, what happens when an object by chance resembles a face? Everyday objects can sometimes, through the accidental positioning of their internal components, appear as faces. This phenomenon is known as face pareidolia. Behavioral experiments have suggested that macaques, like humans, perceive illusory faces in such objects. However, it is an open question whether such stimuli would naturally stimulate neurons residing in cortical face patches. To address this question, we recorded single unit activity from four fMRI-defined face-selective regions: the anterior medial (AM), anterior fundus (AF), prefrontal orbital (PO), and perirhinal cortex (PRh) face patches. We compared neural responses elicited by images of real macaque faces, pareidolia-evoking objects, and matched control objects. Contrary to expectations, we found no evidence of a general preference for pareidolia-evoking objects over control objects. Although a subset of neurons exhibited stronger responses to pareidolia-evoking objects, the population responses to both categories of objects were similar, and collectively much less than to real macaque faces. These results suggest that neural responses in the four regions we tested are principally concerned with the analysis of realistic facial characteristics, whereas the special attention afforded to face-like pareidolia stimuli is supported by activity elsewhere in the brain.
Robson E, Donahue MM, Mably AJ
… +3 more, Demetrovich PG, Hewitt LT, Colgin LL
Prog Neurobiol
· 2025 Feb · PMID 39743170
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Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social i...Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.
In response to stressors, individuals manifest varied behavioral responses directed toward satisfying physiological survival needs. Although the enduring effects of adolescent stress on both humans and animals are well-d...In response to stressors, individuals manifest varied behavioral responses directed toward satisfying physiological survival needs. Although the enduring effects of adolescent stress on both humans and animals are well-documented, the underlying mechanisms remain insufficiently elucidated. Utilizing immunofluorescence, viral injections, and brain slice electrophysiological recordings, we have delineated that heightened excitability among glutamatergic neurons in the basolateral amygdala (BLA) is responsible for inducing heightened exploratory behaviors in adolescent mice subjected to mild, chronic restraint stress. Activation of BLA glutamatergic neurons through chemogenetics increases exploratory behaviors in emotional assessments, whereas inhibition of these neurons diminishes exploratory behaviors in measures such as the open field and elevated plus maze test. Furthermore, an upregulation of glutamate receptor expression and a concomitant downregulation of GABA receptor expression in BLA glutamatergic neurons have been associated with enhanced exploratory behaviors, validated through in vivo receptor antagonists. These findings unveil the protective role of mild stress exposure during adolescence against adversity, providing novel insights for addressing stressful events.
Targeted Recombination in Active Populations (TRAP) represents an effective and extensively applied technique that has earned significant utilization in neuroscience over the past decade, primarily for identifying and mo...Targeted Recombination in Active Populations (TRAP) represents an effective and extensively applied technique that has earned significant utilization in neuroscience over the past decade, primarily for identifying and modulating functionally activated neuronal ensembles associated with diverse behaviors. As epilepsy is a neurological disorder characterized by pathological hyper-excitatory networks, TRAP has already been widely applied in epilepsy research. However, the deployment of TRAP in this field remains underexplored, and there is significant potential for further application and development in epilepsy-related investigations. In this review, we embark on a concise examination of the mechanisms behind several TRAP tools, introduce the current applications of TRAP in epilepsy research, and collate the key advantages as well as limitations of TRAP. Furthermore, we sketch out perspectives on potential applications of TRAP in future epilepsy research, grounded in the present landscape and challenges of the field, as well as the ways TRAP has been embraced in other neuroscience domains.
Inflammation is a major mechanism of photoreceptor cell death in the retina during macular degeneration leading to the blindness. In this study, we investigated the role of the kinase molecule Zap70, which is an inflamma...Inflammation is a major mechanism of photoreceptor cell death in the retina during macular degeneration leading to the blindness. In this study, we investigated the role of the kinase molecule Zap70, which is an inflammatory regulator of the systemic immune system, to elucidate the control mechanism of inflammation in the retina. We observed activated microglial cells migrated and populated the retinal layer following blue LED-induced photoreceptor degeneration and activated microglial cells in the LED-injured retina expressed Zap70, unlike the inactive microglial cells in the normal retina. Visual function was considerably decreased in blue-LED light-exposed mice, and animals with Zap70 mutations were adversely affected. Furthermore, extensive photoreceptor cell death was observed in the SKG mice, bearing a Zap70 mutation that induces autoimmune disease. In the blue-LED light-exposed groups, SKG retinas had significantly higher levels of inflammatory cytokines than those in wild-type mice. Furthermore, regulating Zap70 activity has a significant influence on microglial inflammatory state. We discovered that active microglial cells expressing Zap70 could modify vascular endothelial growth factor A (Vegfa) signaling in primary retinal pigment epithelial (RPE) cells. Our novel study revealed that the production of Zap70 by retinal microglial cells is responsible for inflammatory signals that promote apoptosis in photoreceptor cells. Furthermore, Zap70-positive microglial cells were capable of regulating Vegfa signaling in RPE cells, which matches the hallmark of macular degeneration. Overall, we discovered Zap70's inflammatory activity in the retina, which is necessary for upregulating multiple inflammatory cytokines and cell death. Zap70 represents a novel therapeutic target for treating retinal degeneration.
Neurotransmitter receptors are key molecules in signal transmission in the adult brain, and their precise spatial and temporal balance expressions also play a critical role in normal brain development. However, the speci...Neurotransmitter receptors are key molecules in signal transmission in the adult brain, and their precise spatial and temporal balance expressions also play a critical role in normal brain development. However, the specific balance expression of multiple receptors during hippocampal development is not well characterized. In this study, we used quantitative in vivo receptor autoradiography to measure the distributions and densities of 18 neurotransmitter receptor types in the mouse hippocampal complex at postnatal day 7, and compared them with the expressions of their corresponding encoding genes. We provide a novel and comprehensive characterization of the cyto-, gene, and multireceptor architecture of the developing mouse hippocampal and subicular regions during the developmental period, which typically differs from that in the adult brain. High-density receptor expressions with distinct regional and laminar distributions were observed for AMPA, Kainate, mGluR2/3, GABA, GABA/BZ, α, and A receptors during this specific period, whereas NMDA, GABA, α, M, M, M, nicotinic αβ, 5-HT, 5-HT, D and D/D receptors exhibited relatively low and homogeneous expressions. This specific balance of multiple receptors aligns with regional cytoarchitecture, neurotransmitter distributions, and gene expressions. Moreover, contrasting with previous findings, we detected a high α receptor density, with distinct regional and laminar distribution patterns. A non-covariation differentiation phenomenon between α receptor distributions and corresponding gene expressions is also demonstrated in this early developmental period. The multimodal data provides new insights into understanding the hippocampal development from the perspective of cell, gene, and multireceptor levels, and contributes important resources for further interdisciplinary analyses.
The putamen is thought to generate habitual actions by processing value information relayed from the ventral striatum through the caudate nucleus. However, it is a question what value the putamen neurons process and whet...The putamen is thought to generate habitual actions by processing value information relayed from the ventral striatum through the caudate nucleus. However, it is a question what value the putamen neurons process and whether the putamen receives serially processed value through the striatal structures. We found that neurons in the primate putamen, caudate, and ventral striatum selectively encoded flexibly updated values for adaptive behaviors with similar learning speeds, rather than stably sustained values for habit. In reversal value learning, rostral striatum neurons dynamically adjusted their responses to object values in alignment with changes in saccade reaction times following reversals. Notably, the value acquisition speeds within trials were similar, proposing a parallel value update in each striatal region. However, in stable value retrieval, most did not encode the values for habitual saccades. Our findings suggest that the rostral striatum including the putamen is selectively involved in the parallel processing of cognitive flexibility.
How does the brain track and process rapidly changing sensory information? Current computational accounts suggest that our sensations and decisions arise from the intricate interplay between bottom-up sensory signals and...How does the brain track and process rapidly changing sensory information? Current computational accounts suggest that our sensations and decisions arise from the intricate interplay between bottom-up sensory signals and constantly changing expectations regarding the statistics of the surrounding world. A significant focus of recent research is determining which statistical properties are tracked by the brain as it monitors the rapid progression of sensory information. Here, by combining EEG (three experiments N ≥ 22 each) and computational modelling, we examined how the brain processes rapid and stochastic sound sequences that simulate key aspects of dynamic sensory environments. Passively listening participants were exposed to structured tone-pip arrangements that contained transitions between a range of stochastic patterns. Predictions were guided by a Bayesian predictive inference model. We demonstrate that listeners automatically track the statistics of unfolding sounds, even when these are irrelevant to behaviour. Transitions between sequence patterns drove a shift in the sustained EEG response. This was observed to a range of distributional statistics, and even in situations where behavioural detection of these transitions was at floor. These observations suggest that the modulation of the EEG sustained response reflects a process of belief updating within the brain. By establishing a connection between the outputs of the computational model and the observed brain responses, we demonstrate that the dynamics of these transition-related responses align with the tracking of "precision" - the confidence or reliability assigned to a predicted sensory signal - shedding light on the intricate interplay between the brain's statistical tracking mechanisms and its response dynamics.
The development and refinement of neuronal circuitry allow for stabilized and efficient neural recruitment, supporting adult-like behavioral performance. During adolescence, the maturation of PFC is proposed to be a crit...The development and refinement of neuronal circuitry allow for stabilized and efficient neural recruitment, supporting adult-like behavioral performance. During adolescence, the maturation of PFC is proposed to be a critical period (CP) for executive function, driven by a break in balance between glutamatergic excitation and GABAergic inhibition (E/I) neurotransmission. During CPs, cortical circuitry fine-tunes to improve information processing and reliable responses to stimuli, shifting from spontaneous to evoked activity, enhancing the SNR, and promoting neural synchronization. Harnessing 7 T MR spectroscopy and EEG in a longitudinal cohort (N = 164, ages 10-32 years, 283 neuroimaging sessions), we outline associations between age-related changes in glutamate and GABA neurotransmitters and EEG measures of cortical SNR. We find developmental decreases in spontaneous activity and increases in cortical SNR during our auditory steady state task using 40 Hz stimuli. Decreases in spontaneous activity were associated with glutamate levels in DLPFC, while increases in cortical SNR were associated with more balanced Glu and GABA levels. These changes were associated with improvements in working memory performance. This study provides evidence of CP plasticity in the human PFC during adolescence, leading to stabilized circuitry that allows for the optimal recruitment and integration of multisensory input, resulting in improved executive function.
Short open reading frames (sORFs) are frequently overlooked because of their historical classification as non-coding elements or dismissed as "transcriptional noise". However, advanced genomic and proteomic technologies...Short open reading frames (sORFs) are frequently overlooked because of their historical classification as non-coding elements or dismissed as "transcriptional noise". However, advanced genomic and proteomic technologies have allowed for screening and validating sORFs-encoded peptides, revealing their fundamental regulatory roles in cellular processes and sparking a growing interest in microprotein biology. In neuroscience, microproteins serve as neurotransmitters in signal transmission and regulate metabolism and emotions, exerting pivotal effects on neurological conditions such as nerve injury, neurogenic tumors, inflammation, and neurodegenerative diseases. This review summarizes the origins, characteristics, classifications, and functions of microproteins, focusing on their molecular mechanisms in neurological disorders. Potential applications, future perspectives, and challenges are discussed.
The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD...The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, compelling evidence indicates that purinergic signaling plays a key role in neuro-immune cell functions. The extracellular release of adenosine 5'-triphosphate (ATP), and its breakdown products (ADP and adenosine) provide the versatile basis for complex purinergic signaling through the activation of several families of receptors. G-protein coupled adenosine A receptors, ionotropic P2X and G-protein coupled P2Y receptors for ATP and other nucleotides are abundant and widely distributed in neurons, microglia, and astrocytes of the central nervous system as well as in peripheral immune cells. These receptors are strongly linked to inflammation, with a functional interplay that may influence the intricate purinergic signaling involved in inflammatory responses. In the present review, we examine the roles of the purinergic receptors in neuro-immune cell functions with particular emphasis on AR, P2X4 and P2X7 and their possible relevance to specific neurodegenerative disorders. Understanding the molecular mechanisms governing purinergic receptor interaction will be crucial for advancing the development of effective immunotherapies targeting neurodegenerative diseases.
Luo H, Anderson A, Masuho I
… +4 more, Marron Fernandez de Velasco E, Birnbaumer L, Martemyanov KA, Wickman K
Prog Neurobiol
· 2024 Dec · PMID 39542413
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Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inward...Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inwardly rectifying K (GIRK or Kir3) channels mediate postsynaptic inhibition evoked by G protein-coupled receptors (GPCRs) that signal via inhibitory G proteins. GIRK-dependent signaling is modulated by Regulator of G protein Signaling proteins RGS6 and RGS7, but their selectivity for distinct GPCR-GIRK signaling pathways in defined neurons is unclear. We compared how RGS6 and RGS7 impact GIRK channel regulation by the GABA receptor (GABAR), 5HT receptor (5HTR), and A adenosine receptor (AR) in hippocampal neurons. Our data show that RGS6 and RGS7 make non-redundant contributions to GABAR- and 5HTR-GIRK signaling and compartmentalization and suggest that GPCR-G protein preferences and the substrate bias of RGS proteins, as well as receptor-dependent differences in Gα engagement and effector access, shape GPCR-GIRK signaling dynamics in hippocampal neurons.
Sánchez de la Torre A, Ezquerro-Herce S, Huerga-Gómez A
… +9 more, Sánchez-Martín E, Chara JC, Matute C, Monory K, Mato S, Lutz B, Guzmán M, Aguado T, Palazuelos J
Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is st...Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells. By using conditional genetic mouse models, here we found that cannabinoid CB receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway. Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB-deficient mice. Overall, this study identifies CB receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.
Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordin...Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordinates a range of motor, affective and cognitive processes. Despite well-described circuits and integrative mechanisms, specific changes that underlie cerebellar impairments in ASD remain elusive. Studies in experimental animals have been critical in uncovering molecular pathology and neuro-behavioural correlates, providing a model for investigating complex disease conditions. Herein, we review commonalities and differences of the most extensively characterised genetic lines of ASD with reference to the cerebellum. We revisit structural, functional, and molecular alterations which may contribute to neurobehavioral phenotypes. The cross-model analysis of this study provides an integrated outlook on the role of cerebellar alterations in pathobiology of ASD that may benefit future translational research and development of therapies.
The hypothalamic arcuate nucleus (ARC) contains two main populations of neurons essential for energy homeostasis: neuropeptide Y (NPY) neurons, which are orexigenic and stimulate food intake, and proopiomelanocortin (POM...The hypothalamic arcuate nucleus (ARC) contains two main populations of neurons essential for energy homeostasis: neuropeptide Y (NPY) neurons, which are orexigenic and stimulate food intake, and proopiomelanocortin (POMC) neurons, which have an anorexigenic effect. Located near the blood-brain barrier, ARC neurons sense blood-borne signals such as leptin, insulin, and glucose. Exogenous substances, such as nicotine, can also alter ARC neuron activity and energy balance. Nicotine, an addictive drug used worldwide, inhibits appetite, and reduces body weight, although its mechanisms in regulating ARC neurons are not well understood. Using electrophysiological techniques in brain slices, we investigated the effects of nicotine on POMC and NPY neurons at physiological glucose concentrations. We found that nicotine increased the firing rate of POMC and inhibited NPY neurons. Additionally, nicotine-enhanced glutamatergic inputs to POMC cells and GABAergic inputs to NPY neurons, mediated by α7 and α4β2 nicotinic acetylcholine receptors (nAChRs), respectively. These findings can contribute to the understanding of the anorexigenic effects of nicotine in smokers.
Pizzella A, Penna E, Liu Y
… +7 more, Abate N, Lacivita E, Leopoldo M, Perrone-Capano C, Crispino M, Baudry M, Bi X
Prog Neurobiol
· 2024 Nov · PMID 39481590
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Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectr...Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectrum Disorders (ASD). It is known that stimulation of the serotonin receptor 7 (5-HT7R) can rescue some of the behavioral and neuroplasticity dysfunctions in animal models of Fragile X and Rett syndrome, two pathologies associated with ASD. In view of these observations, we hypothesised that alterations of 5-HT7R signalling might also be involved in AS. To test this hypothesis, we stimulated 5-HT7R with the selective agonist LP-211 to investigate its possible beneficial effects on synaptic dysfunctions and altered behavior in the AS mice model. In mutant mice, we observed impairment of the synaptic machinery of protein synthesis, which was reversed by 5-HT7R activation. Moreover, stimulation of 5-HT7R was able to: i) enhance dendritic spine density in hippocampal neurons, which was reduced in AS mice; ii) restore impaired long-term potentiation (LTP) in hippocampal slices of the AS mice; iii) improve cognitive performance of the mutant animals subjected to the fear conditioning paradigm. Altogether, our results, showing beneficial effects of 5-HT7R stimulation in restoring molecular and cognitive deficits associated with AS, suggest that targeting 5-HT7R could be a promising therapeutic approach for the pathology.