Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons (PNs), largely mediated by synaptic long-term potentiation (LTP). The circuit mechanisms ...underlying cortical LTP remain unclear. In the mouse somatosensory cortex, LTP can be elicited in layer 2/3 PNs by rhythmic whisker stimulation. We dissected the synaptic circuitry underlying this type of plasticity in thalamocortical slices. We found that projections from higher-order, posterior medial thalamic complex (POm) are key to eliciting N-methyl-D-aspartate receptor (NMDAR)-dependent LTP of intracortical synapses. Paired activation of cortical and higher-order thalamocortical inputs increased vasoactive intestinal peptide (VIP) and parvalbumin (PV) interneuron (IN) activity and decreased somatostatin (SST) IN activity, which together disinhibited the PNs. VIP IN-mediated disinhibition was critical for inducing LTP. This study reveals a circuit motif in which higher-order thalamic inputs gate synaptic plasticity via disinhibition. This motif may allow contextual feedback to shape synaptic circuits that process first-order sensory information.
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•Activation of higher-order (HO) thalamic inputs facilitates intracortical LTP•HO inputs increase VIP and PV interneuron (IN) activity and decrease SST IN activity•The activation of VIP INs disinhibits L2/3 pyramidal neurons (PNs)•The HO-to-VIP circuit gates the intracortically driven LTP on PNs
Using ex vivo patch-clamp recordings, optogenetics, and chemogenetics, Williams and Holtmaat dissect the circuits underlying sensory-driven LTP in the cortex. This reveals a circuit motif in which higher-order thalamocortical input gates plasticity of intracortical synapses via VIP-mediated disinhibition.
Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates ...microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), ...is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
Synapses between neurons are malleable biochemical structures, strengthening and diminishing over time dependent on the type of information they receive. This phenomenon known as synaptic plasticity ...underlies learning and memory, and its different forms, long‐term potentiation (LTP) and long‐term depression (LTD), perform varied cognitive roles in reinforcement, relearning and associating memories. Moreover, both LTP and LTD can exist in an early transient form (early‐LTP/LTD) or a late persistent form (late‐LTP/LTD), which are triggered by different induction protocols, and also differ in their dependence on protein synthesis and the involvement of key molecular players. Beyond homosynaptic modifications, synapses can also interact with one another. This is encapsulated in the synaptic tagging and capture hypothesis (STC), where synapses expressing early‐LTP/LTD present a ‘tag’ that can capture the protein synthesis products generated during a temporally proximal late‐LTP/LTD induction. This ‘tagging’ phenomenon forms the framework of synaptic interactions in various conditions and accounts for the cellular basis of the time‐dependent associativity of short‐lasting and long‐lasting memories. All these synaptic modifications take place under controlled neuronal conditions, regulated by subcellular elements such as epigenetic regulation, proteasomal degradation and neuromodulatory signals. Here, we review current understanding of the different forms of synaptic plasticity and its regulatory mechanisms in the hippocampus, a brain region critical for memory formation. We also discuss expression of plasticity in hippocampal CA2 area, a long‐overlooked narrow hippocampal subfield and the behavioural correlate of STC. Lastly, we put forth perspectives for an integrated view of memory representation in synapses.
Synaptic plasticity permits bidirectional modification of synapses and likely is a cellular correlate of learning and memory. Synaptic tagging and capture enables synapses to interact with one another, underpinning associative learning. We describe how several key molecular players and cellular events promote, restrict or modulate homosynaptic and heterosynaptic forms of plasticity. Focusing on the hippocampus, we discuss recent advances in synaptic plasticity, its molecular interactions and behavioural implications.
MicroRNAs play a pivotal role in rapid, dynamic, and spatiotemporal modulation of synaptic functions. Among them, recent emerging evidence highlights that microRNA‐181a (miR‐181a) is particularly ...abundant in hippocampal neurons and controls the expression of key plasticity‐related proteins at synapses. We have previously demonstrated that miR‐181a was upregulated in the hippocampus of a mouse model of Alzheimer's disease (AD) and correlated with reduced levels of plasticity‐related proteins. Here, we further investigated the underlying mechanisms by which miR‐181a negatively modulated synaptic plasticity and memory. In primary hippocampal cultures, we found that an activity‐dependent upregulation of the microRNA‐regulating protein, translin, correlated with reduction of miR‐181a upon chemical long‐term potentiation (cLTP), which induced upregulation of GluA2, a predicted target for miR‐181a, and other plasticity‐related proteins. Additionally, Aβ treatment inhibited cLTP‐dependent induction of translin and subsequent reduction of miR‐181a, and cotreatment with miR‐181a antagomir effectively reversed the effects elicited by Aβ but did not rescue translin levels, suggesting that the activity‐dependent upregulation of translin was upstream of miR‐181a. In mice, a learning episode markedly decreased miR‐181a in the hippocampus and raised the protein levels of GluA2. Lastly, we observed that inhibition of miR‐181a alleviated memory deficits and increased GluA2 and GluA1 levels, without restoring translin, in the 3xTg‐AD model. Taken together, our results indicate that miR‐181a is a major negative regulator of the cellular events that underlie synaptic plasticity and memory through AMPA receptors, and importantly, Aβ disrupts this process by suppressing translin and leads to synaptic dysfunction and memory impairments in AD.
In the hippocampus, neuronal stimulation produces upregulation of translin, reduction of miR‐181a, and an increase in the protein levels of its target GluA2 leading to synaptic plasticity. This plasticity mechanism is impaired by amyloid‐beta (Aβ) toxic species.
Regulation of microRNA (miRNA) expression and function in the context of activity‐dependent synaptic plasticity in the adult brain is little understood. Here, we examined miRNA expression during ...long‐term potentiation (LTP) in the dentate gyrus of adult anesthetized rats. Microarray expression profiling identified a subpopulation of regulated mature miRNAs 2 h after the induction of LTP by high‐frequency stimulation (HFS) of the medial perforant pathway. Real‐time polymerase chain reaction analysis confirmed modest upregulation of miR‐132 and miR‐212, and downregulation of miR‐219, while no changes occurred at 10 min post‐HFS. Surprisingly, pharmacological blockade of N‐methyl‐d‐aspartate receptor (NMDAR)‐dependent LTP enhanced expression of these mature miRNAs. This HFS‐evoked expression was abolished by local infusion of the group 1 metabotropic glutamate receptor (mGluR) antagonist, (RS)‐1‐aminoindan‐1,5‐dicarboxylic acid (AIDA). AIDA had no effect on LTP induction or maintenance, but blocked activity‐dependent depotentiation of LTP. Turning to the analysis of miRNA precursors, we show that HFS elicits 50‐fold elevations of primary (pri) and precursor (pre) miR‐132/212 that is transcription dependent and mGluR dependent, but insensitive to NMDAR blockade. Primary miR‐219 expression was unchanged during LTP. In situ hybridization showed upregulation of the pri‐miR‐132/212 cluster restricted to dentate granule cell somata. Thus, HFS induces transcription miR‐132/212 that is mGluR dependent and functionally correlated with depotentiation rather than LTP. In contrast, NMDAR activation selectively downregulates mature miR‐132, ‐212 and ‐219 levels, indicating accelerated decay of these mature miRNAs. This study demonstrates differential regulation of primary and mature miRNA expression by mGluR and NMDAR signaling following LTP induction, the function of which remains to be defined.
AMPA receptors (AMPARs) are fundamental elements in excitatory synaptic transmission and synaptic plasticity in the CNS. Long term potentiation (LTP), a form of synaptic plasticity which contributes ...to learning and memory formation, relies on the accumulation of AMPARs at the postsynapse. This phenomenon requires the coordinated recruitment of different elements in the AMPAR complex. Based on recent research reviewed herein, we propose an updated AMPAR trafficking and LTP model which incorporates both extracellular as well as intracellular mechanisms.
This article is part of the special Issue on ‘Glutamate Receptors – AMPA receptors’.
•Long-term potentiation (LTP) of excitatory synapses underlies learning and memory.•AMPA receptor (AMPAR) accumulation is essential for LTP at CA3-CA1 synapses.•The extracellular AMPAR amino-terminal domain is required for synaptic trafficking.•Interactions between TARPs and MAGUK scaffolding proteins dock AMPARs at synapses.•Extra- and intracellular mechanisms enable AMPAR trafficking in synaptic plasticity.
Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. ...Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (L-LTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research.
This article is part of the Special Issue entitled ‘BDNF Regulation of Synaptic Structure, Function, and Plasticity’.
•BDNF-TrkB regulates late LTP through diverse mechanisms.•TrkB-coupled translational control and actin cytoskeletal regulation.•BDNF rescue of late LTP.•Brain region-specific mechanisms.•Pathway cross-talk and signal bias.
This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal ...studies in the first phase of the six‐decade span of this review firmly established the cellular basis of behavior – a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long‐term potentiation and long‐term depression, was then discovered as being important for local circuit refinement in the context of memory formation and behavioral change and stabilization in the mammalian central nervous system. Direct demonstration of plasticity of neuronal circuit function in vivo, for example, hippocampal neurons forming place cell firing patterns, extended this concept. However, additional neurophysiologic and computational studies demonstrated that circuit development and stabilization additionally relies on non‐Hebbian, homoeostatic, forms of plasticity, such as synaptic scaling and control of membrane intrinsic properties. Activity‐dependent neurodevelopment was found to be associated with cell‐wide adjustments in post‐synaptic receptor density, and found to occur in conjunction with synaptic pruning. Pioneering cellular neurophysiologic studies demonstrated the critical roles of transmembrane signal transduction, NMDA receptor regulation, regulation of neural membrane biophysical properties, and back‐propagating action potential in critical time‐dependent coincidence detection in behavior‐modifying circuits. Concerning the molecular mechanisms underlying these processes, regulation of gene transcription was found to serve as a bridge between experience and behavioral change, closing the ‘nature versus nurture’ divide. Both active DNA (de)methylation and regulation of chromatin structure have been validated as crucial regulators of gene transcription during learning. The discovery of protein synthesis dependence on the acquisition of behavioral change was an influential discovery in the neurochemistry of behavioral modification. Higher order cognitive functions such as decision making and spatial and language learning were also discovered to hinge on neural plasticity mechanisms. The role of disruption of these processes in intellectual disabilities, memory disorders, and drug addiction has recently been clarified based on modern genetic techniques, including in the human.
The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life‐span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as ‘conceptual advances’, as viewed by the author. The fifteen areas are delineated in the figure above.
This article is part of the 60th Anniversary special issue.
The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life‐span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as ‘conceptual advances’, as viewed by the author. The fifteen areas are delineated in the figure above.
This article is part of the 60th Anniversary special issue.
Docosahexaenoic acid (DHA, 22:6n-3), the major polyunsaturated fatty acid accumulated in the brain during development, has been implicated in learning and memory, but underlying cellular mechanisms ...are not clearly understood. Here, we demonstrate that DHA significantly affects hippocampal neuronal development and synaptic function in developing hippocampi. In embryonic neuronal cultures, DHA supplementation uniquely promoted neurite growth, synapsin puncta formation and synaptic protein expression, particularly synapsins and glutamate receptors. In DHA-supplemented neurons, spontaneous synaptic activity was significantly increased, mostly because of enhanced glutamatergic synaptic activity. Conversely, hippocampal neurons from DHA-depleted fetuses showed inhibited neurite growth and synaptogenesis. Furthermore, n-3 fatty acid deprivation during development resulted in marked decreases of synapsins and glutamate receptor subunits in the hippocampi of 18-day-old pups with concomitant impairment of long-term potentiation, a cellular mechanism underlying learning and memory. While levels of synapsins and NMDA receptor subunit NR2A were decreased in most hippocampal regions, NR2A expression was particularly reduced in CA3, suggesting possible role of DHA in CA3-NMDA receptor-dependent learning and memory processes. The DHA-induced neurite growth, synaptogenesis, synapsin, and glutamate receptor expression, and glutamatergic synaptic function may represent important cellular aspects supporting the hippocampus-related cognitive function improved by DHA.
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