Synaptic Changes Research Articles

Detection of a temporal salient object benefits from visual stimulus-specific adaptation in avian midbrain inhibitory nucleus.

Food and predators are the most noteworthy objects for the basic survival of wild animals, and both are often deviant in both spatial and temporal domains and quickly attract an animal's attention. Although stimulus-specific adaptation (SSA) is considered a potential neural basis of salient sound detection in the temporal domain, related research on visual SSA is limited and its relationship with temporal saliency is uncertain. The avian nucleus isthmi pars magnocellularis (Imc), which is central to midbrain selective attention network, is an ideal site to investigate the neural correlate of visual SSA and detection of a salient object in the time domain. Here, the constant order paradigm was applied to explore the visual SSA in the Imc of pigeons. The results showed that the firing rates of Imc neurons gradually decrease with repetitions of motion in the same direction, but recover when a motion in a deviant direction is presented, implying visual SSA to the direction of a moving object. Furthermore, enhanced response for an object moving in other directions that were not presented ever in the paradigm is also observed. To verify the neural mechanism underlying these phenomena, we introduced a neural computation model involving a recoverable synaptic change with a "center-surround" pattern to reproduce the visual SSA and temporal saliency for the moving object. These results suggest that the Imc produces visual SSA to motion direction, allowing temporal salient object detection, which may facilitate the detection of the sudden appearance of a predator.

The synaptic hypothesis of schizophrenia version III: a master mechanism.

The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there has been a step-change in the evidence available, and some tenets of earlier versions are not supported by recent findings. Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. We then consider the mechanism that could underlie synaptic changes and update the hypothesis. Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss. Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. Based on this evidence, we propose version III of the synaptic hypothesis. This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. It accounts for the typical onset of schizophrenia in adolescence/early adulthood, its major risk factors, and symptoms, and identifies potential synaptic, microglial and immune targets for treatment.

Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder

RNA modifications known as epitranscriptomics have emerged as a novel layer of transcriptomic regulation. Like the well-studied epigenetic modifications characterized in DNA and on histone-tails, they have been shown to regulate activity-dependent gene expression and play a vital role in shaping synaptic connections in response to external stimuli. Among the hundreds of known RNA modifications, N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes. Through recognition of its binding proteins, m6A can regulate various aspects of mRNA metabolism and is essential for maintaining higher brain functions. Indeed, m6A is highly enriched in synapses and is involved in neuronal plasticity, learning and memory, and adult neurogenesis. m6A can also respond to environmental stimuli, suggesting an important role in linking molecular and behavioral stress. This review summarizes key findings from fields related to major depressive disorder (MDD) including stress and learning and memory, which suggest that activity-dependent m6A changes may, directly and indirectly, contribute to synaptic connectivity changes underlying MDD. Furthermore, we will highlight the roles of m6A and FTO, a m6A eraser, in the context of depressive-like behaviors. Although we have only begun to explore m6A in the context of MDD and psychiatry, elucidating a link between m6A and MDD presents a novel molecular mechanism underlying MDD pathogenesis.

Sex-specificities in offspring neurodevelopment and behaviour upon maternal glycation: Putative underlying neurometabolic and synaptic changes

AimLactation is an important programming window for metabolic disease and neuronal alterations later in life. We aimed to study the effect of maternal glycation during lactation on offspring neurodevelopment and behaviour, assessing possible sex differences and underpinning molecular players. MethodsFemale Wistar rats were treated with Glyoxalase-1 inhibitor S-p-Bromobenzylguthione cyclopentyl diester (BBGC 5 mg/kg). A control and vehicle group treated with dimethyl sulfoxide were also considered. Male and female offspring were tested at infancy for neurodevelopment hallmarks. After weaning, triglycerides and total antioxidant capacity were measured in breast milk. At adolescence, offspring were tested for locomotor ability, anxious-like behaviour, and recognition memory. Metabolic parameters were assessed, and the hippocampus and prefrontal cortex were collected for molecular analysis. Key findingsMaternal glycation reduced triglycerides and total antioxidant capacity levels in breast milk. At infancy, both male and female offspring presented an anticipation on the achievement of neurodevelopmental milestones. At adolescence, male offspring exposed to maternal glycation presented hyperlocomotion, whereas offspring of both sexes presented a risk-taking phenotype, accompanied by increase GABAA receptor levels in the hippocampus. Females also demonstrated GABAA and PSD-95 changes in prefrontal cortex. Furthermore, lower levels of GLO1 and consequently higher accumulation of AGES were also observed in both male and female offspring hippocampus. SignificanceEarly exposure to maternal glycation induces changes in milk composition leading to neurodevelopment changes at infancy, and sex-specific behavioural and neurometabolic changes at adolescence, further evidencing that lactation period is a critical metabolic programming window and in sculpting behaviour.

Paternal Deprivation and Female Biparental Family Rearing Induce Dendritic and Synaptic Changes in Octodon degus: II. Nucleus Accumbens

While the majority of studies on the importance of parental caregiving on offspring behavioral and brain development focus on the role of the mother, the paternal contribution is still an understudied topic. We investigated if growing up without paternal care affects dendritic and synaptic development in the nucleus accumbens of male and female offspring and if replacement of the father by a female caregiver “compensates” the impact of paternal deprivation. We compared (a) biparental rearing by father and mother, (b) monoparental care by a single mother, and (c) biparental rearing by two female caregivers. Quantitative analysis of medium-sized neurons in the nucleus accumbens revealed that growing up without father resulted in reduced spine number in both male and female offspring in the core region, whereas spine frequency was only reduced in females. In the shell region, reduced spine frequency was only found in males growing up in a monoparental environment. Replacement of the father by a female caregiver did not “protect” against the effects of paternal deprivation, indicating a critical impact of paternal care behavior on the development and maturation of neuronal networks in the nucleus accumbens.

From circuits to behavior: Amygdala dysfunction in fragile X syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a repeat expansion mutation in the promotor region of the FMR1 gene resulting in transcriptional silencing and loss of function of fragile X messenger ribonucleoprotein 1 protein (FMRP). FMRP has a well-defined role in the early development of the brain. Thus, loss of the FMRP has well-known consequences for normal cellular and synaptic development leading to a variety of neuropsychiatric disorders including an increased prevalence of amygdala-based disorders. Despite our detailed understanding of the pathophysiology of FXS, the precise cellular and circuit-level underpinnings of amygdala-based disorders is incompletely understood. In this review, we discuss the development of the amygdala, the role of neuromodulation in the critical period plasticity, and recent advances in our understanding of how synaptic and circuit-level changes in the basolateral amygdala contribute to the behavioral manifestations seen in FXS.

Neural dynamic transitions caused by changes of synaptic strength in heterogeneous networks

Sleep-dependent memory consolidation (SDMC) is an unaddressed and challenging functional issue regarding neural dynamics. Based on experimental findings, the synaptic homeostasis hypothesis for understanding SDMC implies a link between changes of synaptic strength and transitions of neural dynamics (including tonic and bursting activities). However, the causality of the link has been unclear. Recently, it has been found that, the synaptic changes can cause the dynamical transitions and so can produce the slow-wave activity (SWA) similar to that observed during sleep in a homogeneous network (Zhou et al., 2021). Since many real neural networks are heterogeneous in topology, we herein further investigated the transitions and the SWA driven by the synaptic changes in heterogeneous networks. It was found that synaptic changes can also cause the dynamical transitions and the SWA. Differently, the transitions in heterogeneous networks are hierarchical for neurons with different degrees, whether in electrically or chemically coupled networks. The critical synaptic strengths related to the transitions for neurons depend strongly on their degrees. The larger the degree, the smaller the critical synaptic strength. We showed that, they obey power-law relations, both in electrically coupled networks and in chemically coupled networks in the presence of inhibitory synapses. Particularly, it was found that the networked critical synaptic strength depends only on the networked maximum degree in electrically coupled networks. We showed, both numerically and analytically, that they also satisfy a power-law function. In general, our study revealed a possible causal relationship between changes of synaptic strength and transitions of neural dynamics in heterogeneous networks. Further interesting and challenging investigations are briefly discussed as well.

Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer's Disease.

Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer's Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1-6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Effects of glycogen synthase kinase-3β activity inhibition on cognitive, behavioral, and hippocampal ultrastructural deficits in adulthood associated with adolescent methamphetamine exposure.

Glycogen synthase kinase-3β (GSK3β) has been implicated in the maintenance of synaptic plasticity, memory process, and psychostimulant-induced behavioral effects. Hyperactive GSK3β in the Cornu Ammonis 1 (CA1) subregion of the dorsal hippocampus (DHP) was associated with adolescent methamphetamine (METH) exposure-induced behavioral and cognitive deficits in adulthood. This study aimed to evaluate the possible therapeutic effects of GSK3β inhibition in adulthood on adolescent METH exposure-induced long-term neurobiological deficits. Adolescent male mice were treated with METH from postnatal day (PND) 45-51. In adulthood, three intervention protocols (acute lithium chloride systemic administration, chronic lithium chloride systemic administration, and chronic SB216763 administration within CA1) were used for GSK3β activity inhibition. The effect of GSK3β intervention on cognition, behavior, and GSK3β activity and synaptic ultrastructure in the DHP CA1 subregion were detected in adulthood. In adulthood, all three interventions reduced adolescent METH exposure-induced hyperactivity (PND97), while only chronic systemic and chronic within CA1 administration ameliorated the induced impairments in spatial (PND99), social (PND101) and object (PND103) recognition memory. In addition, although three interventions reversed the aberrant GSK3β activity in the DHP CA1 subregion (PND104), only chronic systemic and chronic within CA1 administration rescued adolescent METH exposure-induced synaptic ultrastructure changes in the DHP CA1 subregion (PND104) in adulthood. Rescuing synaptic ultrastructural abnormalities in the dHIP CA1 subregion by chronic administration of a GSK3β inhibitor may be a suitable therapeutic strategy for the treatment of behavioral and cognitive deficits in adulthood associated with adolescent METH abuse.

The mitochondria-targeted small molecule SS31 delays progression of behavioral deficits by attenuating β-amyloid plaque formation and mitochondrial/synaptic deterioration in APP/PS1 mice

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive dysfunction and an impaired ability to carry out daily life functions. Mitochondrial dysfunction and β-amyloid (Aβ) deposition are the most common causes of AD. Antioxidants have been shown to delay brain aging and AD development; however, it remains unknown whether the antioxidant peptide SS31 can protect mitochondrial and synaptic function and delay the progression of behavioral deficits in early-stage AD in vivo. Therefore, in this study we compared mitochondrial and synaptic changes, as well as the protective effects of SS31, in APP/PS1 transgenic mice and C57BL/6J control mice. The APP/PS1 transgenic mice exhibited elevated expression of Aβ40/Aβ42 and mitochondrial fission protein DLP1 and reduced expression of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) reductions, as well as increased levels of neuronal apoptosis and ROS in the hippocampus, and long-term treatment with SS31 reversed these effects. Furthermore, the cognitive impairments observed in APP/PS1 transgenic mice were reversed by SS31 treatment. Our findings show that SS31 lowers ROS and Aβ levels, protecting mitochondrial homeostasis and synaptic integrity, and ultimately improving behavioral deficits in early-stage AD. This suggests that SS31 is a potential pharmacological agent for treating or slowing the progression of AD.

A single dose of cocaine raises SV2A density in hippocampus of adolescent rats.

Cocaine is a highly addictive psychostimulant that affects synaptic activity with structural and functional adaptations of neurons. The transmembrane synaptic vesicle glycoprotein 2A (SV2A) of pre-synaptic vesicles is commonly used to measure synaptic density, as a novel approach to the detection of synaptic changes. We do not know if a single dose of cocaine suffices to affect pre-synaptic SV2A density, especially during adolescence when synapses undergo intense maturation. Here, we explored potential changes of pre-synaptic SV2A density in target brain areas associated with the cocaine-induced boost of dopaminergic neurotransmission, specifically testing if the effects would last after the return of dopamine levels to baseline. We administered cocaine (20 mg/kg i.p.) or saline to rats in early adolescence, tested their activity levels and removed the brains 1 hour and 7 days after injection. To evaluate immediate and lasting effects, we did autoradiography with [3H]UCB-J, a specific tracer for SV2A, in medial prefrontal cortex, striatum, nucleus accumbens, amygdala, and dorsal and ventral areas of hippocampus. We also measured the striatal binding of [3H]GBR-12935 to test cocaine's occupancy of the dopamine transporter at both times of study. We found a significant increase of [3H]UCB-J binding in the dorsal and ventral sections of hippocampus 7 days after the cocaine administration compared to saline-injected rats, but no differences 1 hour after the injection. The [3H]GBR-12935 binding remained unchanged at both times. Cocaine provoked lasting changes of hippocampal synaptic SV2A density after a single exposure during adolescence.

Modelling the contributions to hyperexcitability in a mouse model of Alzheimer's disease.

Neuronal hyperexcitability is a pathological characteristic of Alzheimer's disease (AD). Three main mechanisms have been proposed to explain it: (i) dendritic degeneration leading to increased input resistance, (ii) ion channel changes leading to enhanced intrinsic excitability, and (iii) synaptic changes leading to excitation-inhibition (E/I) imbalance. However, the relative contribution of these mechanisms is not fully understood. Therefore, we performed biophysically realistic multi-compartmental modelling of neuronal excitability in reconstructed CA1 pyramidal neurons from wild-type and APP/PS1mice, a well-established animal model of AD. We show that, for synaptic activation, the excitability-promoting effects of dendritic degeneration are cancelled out by decreased excitation due to synaptic loss. We find an interesting balance between excitability regulation and an enhanced degeneration in the basal dendrites of APP/PS1 cells, potentially leading to increased excitation by the apical but decreased excitation by the basal Schaffer collateral pathway. Furthermore, our simulations reveal three pathomechanistic scenarios that can account for the experimentally observed increase in firing and bursting of CA1 pyramidal neurons in APP/PS1mice: scenario 1: enhanced E/I ratio; scenario 2: alteration of intrinsic ion channels (IAHP down-regulated; INap , INa and ICaT up-regulated) in addition to enhanced E/I ratio; and scenario 3: increased excitatory burst input. Our work supports the hypothesis that pathological network and ion channel changes are major contributors to neuronal hyperexcitability in AD. Overall, our results are in line with the concept of multi-causality according to which multiple different disruptions are separately sufficient but no single particular disruption is necessary for neuronal hyperexcitability. KEY POINTS: This work presents simulations of synaptically driven responses in pyramidal cells (PCs) with Alzheimer's disease (AD)-related dendritic degeneration. Dendritic degeneration alone alters PC responses to layer-specific input but additional pathomechanistic scenarios are required to explain neuronal hyperexcitability in AD as follows. Possible scenario 1: AD-related increased excitatory input together with decreased inhibitory input (E/I imbalance) can lead to hyperexcitability in PCs. Possible scenario 2: changes in E/I balance combined with altered ion channel properties can account for hyperexcitability in AD. Possible scenario 3: burst hyperactivity of the surrounding network can explain hyperexcitability of PCs during AD.

Plastic changes induced by muscle focal vibration: A possible mechanism for long-term motor improvements.

Repetitive focal vibrations can induce positive and persistent after-effects. There is still no satisfactory interpretation of the underlying mechanisms. A rationale, which can provide consistency among different results, is highly desirable to guide both the use of the application and future research. To date, interpretive models are formulated to justify the results, depending on the specific protocol adopted. Indeed, protocol parameters, such as stimulus intensity and frequency, intervention time and administration period, are variable among different studies. However, in this article, we have identified features of the protocols that may allow us to suggest a possible common mechanism underlying the effectiveness of focal vibration under different physiologic and pathologic conditions. Since repetitive focal muscle vibration induces powerful and prolonged activation of muscle proprioceptors, we hypothesize that this intense activation generates adaptive synaptic changes along sensory and motor circuits. This may lead to long-term synaptic potentiation in the central network, inducing an enhancement of the learning capability. The plastic event could increase proprioceptive discriminative ability and accuracy of the spatial reference frame and, consequently, improve motor planning and execution for different motor functions and in the presence of different motor dysfunctions. The proposed mechanism may explain the surprising and sometimes particularly rapid improvements in motor execution in healthy and diseased individuals, regardless of specific physical training. This hypothetic mechanism may require experimental evidence and could lead to extend and adapt the application of the "learning without training" paradigms to other functional and recovery needs.

Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain

Increased low frequency cortical oscillations are observed in people with neuropathic pain, but the cause of such elevated cortical oscillations and their impact on pain development remain unclear. By imaging neuronal activity in a spared nerve injury (SNI) mouse model of neuropathic pain, we show that neurons in dorsal root ganglia (DRG) and somatosensory cortex (S1) exhibit synchronized activity after peripheral nerve injury. Notably, synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations. This DRG synchrony is initiated by axotomized neurons and mediated by local purinergic signaling at the site of nerve injury. We further show that synchronized DRG activity after SNI is responsible for increasing low frequency cortical oscillations and synaptic remodeling in S1, as well as for inducing animals’ pain-like behaviors. In naive mice, enhancing the synchrony, not the level, of DRG neuronal activity causes synaptic changes in S1 and pain-like behaviors similar to SNI mice. Taken together, these results reveal the critical role of synchronized DRG neuronal activity in increasing cortical plasticity and oscillations in a neuropathic pain model. These findings also suggest the potential importance of detection and suppression of elevated cortical oscillations in neuropathic pain states.

Generalized extinction of fear memory depends on co-allocation of synaptic plasticity in dendrites

Memories can be modified by new experience in a specific or generalized manner. Changes in synaptic connections are crucial for memory storage, but it remains unknown how synaptic changes associated with different memories are distributed within neuronal circuits and how such distributions affect specific or generalized modification by novel experience. Here we show that fear conditioning with two different auditory stimuli (CS) and footshocks (US) induces dendritic spine elimination mainly on different dendritic branches of layer 5 pyramidal neurons in the mouse motor cortex. Subsequent fear extinction causes CS-specific spine formation and extinction of freezing behavior. In contrast, spine elimination induced by fear conditioning with >2 different CS-USs often co-exists on the same dendritic branches. Fear extinction induces CS-nonspecific spine formation and generalized fear extinction. Moreover, activation of somatostatin-expressing interneurons increases the occurrence of spine elimination induced by different CS-USs on the same dendritic branches and facilitates the generalization of fear extinction. These findings suggest that specific or generalized modification of existing memories by new experience depends on whether synaptic changes induced by previous experiences are segregated or co-exist at the level of individual dendritic branches.

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

Synapse loss has been considered as a major pathological change in Alzheimer’s disease (AD). It remains unclear about whether and how synapse loss relates to functional and structural connectivity dysfunction in AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using 18F-SynVesT-1 PET to evaluate synaptic alterations in 33 participants with AD, 31 with mild cognitive impairment (MCI), and 30 controls. We examined the correlation between synaptic density and cognitive function. Functional MRI was performed to analyze functional connectivity in lower synaptic density regions. We tracked the white matter tracts between impaired functional connectivity regions using Diffusion MRI. In AD group, lower synaptic density in bilateral cortex and hippocampus was found when compared with controls. The synaptic density changes in right insular cortex and bilateral caudal middle frontal gyrus (MFG) were correlated with cognitive decline. Among them, right MFG synaptic density was positively associated with right MFG - bilateral superior frontal gyrus (SFG) functional connectivity. AD had lower probability of tract (POT) between right MFG and SFG than controls, which was significantly associated with global cognition. These findings provide evidence supporting synapse loss contributes to functional and related structural connectivity alterations underlying cognitive impairment of AD.

Synaptic Plasticity Abnormalities in Fetal Alcohol Spectrum Disorders.

The brain's ability to strengthen or weaken synaptic connections is often termed synaptic plasticity. It has been shown to function in brain remodeling following different types of brain damage (e.g., drugs of abuse, alcohol use disorders, neurodegenerative diseases, and inflammatory conditions). Although synaptic plasticity mechanisms have been extensively studied, how neural plasticity can influence neurobehavioral abnormalities in alcohol use disorders (AUDs) is far from being completely understood. Alcohol use during pregnancy and its harmful effects on the developing offspring are major public health, social, and economic challenges. The significant attribute of prenatal alcohol exposure on offspring is damage to the central nervous system (CNS), causing a range of synaptic structural, functional, and behavioral impairments, collectively called fetal alcohol spectrum disorder (FASD). Although the synaptic mechanisms in FASD are limited, emerging evidence suggests that FASD pathogenesis involves altering a set of molecules involved in neurotransmission, myelination, and neuroinflammation. These studies identify several immediate and long-lasting changes using many molecular approaches that are essential for synaptic plasticity and cognitive function. Therefore, they can offer potential synaptic targets for the many neurobehavioral abnormalities observed in FASD. In this review, we discuss the substantial research progress in different aspects of synaptic and molecular changes that can shed light on the mechanism of synaptic dysfunction in FASD. Increasing our understanding of the synaptic changes in FASD will significantly advance our knowledge and could provide a basis for finding novel therapeutic targets and innovative treatment strategies.

Elevated insulin growth factor-1 in dentate gyrus induces cognitive deficits in pre-term newborns.

Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits and that these effects are mediated by insulin growth factor-1 (IGF1). Nonmaternal care of premature rabbits increased the number of granule cells and interneurons and reduced neurogenesis, suggesting accelerated premature maturation of DG. However, the density of glutamatergic synapses, mature dendritic spines, and synaptic transmission were reduced in preterm kits compared with full-term controls, indicating that premature synaptic maturation was abnormal. These findings were consistent with cognitive deficits observed in premature rabbits and appeared to be driven by transcriptomic changes in the granule cells. Preterm kits displayed reduced weight, elevated serum cortisol and growth hormone, and higher IGF1 expression in the liver and DG relative to full-term controls. Importantly, blocking IGF-1 receptor in premature kits restored cognitive deficits, increased the density of glutamatergic puncta, and rescued NR2B and PSD95 levels in the DG. Hence, IGF1 inhibition alleviates prematurity-induced cognitive dysfunction and synaptic changes in the DG through modulation of NR2B and PSD95. The study identifies a novel strategy to potentially rescue DG maldevelopment and cognitive dysfunction in premature infants under stress in NICUs.

Droplet-based transcriptome profiling of individual synapses.

Synapses are crucial structures that mediate signal transmission between neurons in complex neural circuits and display considerable morphological and electrophysiological heterogeneity. So far we still lack a high-throughput method to profile the molecular heterogeneity among individual synapses. In the present study, we develop a droplet-based single-cell (sc) total-RNA-sequencing platform, called Multiple-Annealing-and-Tailing-based Quantitative scRNA-seq in Droplets, for transcriptome profiling of individual neurites, primarily composed of synaptosomes. In the synaptosome transcriptome, or 'synaptome', profiling of both mouse and human brain samples, we detect subclusters among synaptosomes that are associated with neuronal subtypes and characterize the landscape of transcript splicing that occurs within synapses. We extend synaptome profiling to synaptopathy in an Alzheimer's disease (AD) mouse model and discover AD-associated synaptic gene expression changes that cannot be detected by single-nucleus transcriptome profiling. Overall, our results show that this platform provides a high-throughput, single-synaptosome transcriptome profiling tool that will facilitate future discoveries in neuroscience.

Fmr1-KO mice failure to detect object novelty associates with a post-test decrease of structural and synaptic plasticity upstream of the hippocampus

Mice with deletion of the FMR1 gene show episodic memory impairments and exhibit dendritic spines and synaptic plasticity defects prevalently identified in non-training conditions. Based on evidence that synaptic changes associated with normal or abnormal memory emerge when mice are cognitively challenged, here we examine whether, and how, fragile entorhinal and hippocampal synapses are remodeled when mice succeed or fail to learn. We trained Fmr1 knockout (KO) and wild-type C57BL/6J (WT) mice in the novel object recognition (NOR) paradigm with 1 h or 24 h training-to-test intervals and then assessed whether varying the time between the presentation of similar and different objects modulates NOR performance and plasticity along the entorhinal cortex-hippocampus axis. At the 1 h-interval, KO mice failed to discriminate the novel object, showed a collapse of spines in the lateral entorhinal cortex (LEC), and of long-term potentiation (LTP) in the lateral perforant path (LPP), but a normal increase in hippocampal spines. At the 24 h, they exhibited intact NOR performance, typical LEC and hippocampal spines, and exaggerated LPP-LTP. Our findings reveal that the inability of mice to detect object novelty primarily stands in their impediment to elaborate, and convey to the hippocampus, sensory/perceptive object representations.