Increase In Synaptic Strength Research Articles

Evidence for sleep-dependent synaptic renormalization in mouse pups.

In adolescent and adult brains several molecular, electrophysiological, and ultrastructural measures of synaptic strength are higher after wake than after sleep [1, 2]. These results support the proposal that a core function of sleep is to renormalize the increase in synaptic strength associated with ongoing learning during wake, to reestablish cellular homeostasis and avoid runaway potentiation, synaptic saturation, and memory interference [2, 3]. Before adolescence however, when the brain is still growing and many new synapses are forming, sleep is widely believed to promote synapse formation and growth. To assess the role of sleep on synapses early in life, we studied 2-week-old mouse pups (both sexes) whose brain is still undergoing significant developmental changes, but in which sleep and wake are easy to recognize. In two strains (CD-1, YFP-H) we found that pups spend ~50% of the day asleep and show an immediate increase in total sleep duration after a few hours of enforced wake, indicative of sleep homeostasis. In YFP-H pups we then used serial block-face electron microscopy to examine whether the axon-spine interface (ASI), an ultrastructural marker of synaptic strength, changes between wake and sleep. We found that the ASI of cortical synapses (layer 2, motor cortex) was on average 33.9% smaller after sleep relative to after extended wake and the differences between conditions were consistent with multiplicative scaling. Thus, the need for sleep-dependent synaptic renormalization may apply also to the young, pre-weaned cerebral cortex, at least in the superficial layers of the primary motor area.

A role for Numb in Protein kinase M (PKM)-mediated increase in surface AMPA receptors during facilitation in Aplysia.

There is considerable evidence from both vertebrates and invertebrates that persistently active protein kinases maintain changes in synaptic strength that underlie memory. In the hermaphrodite marine mollusk, Aplysia californica, truncated forms of protein kinase C (PKC) termed protein kinase Ms have been implicated in both intermediate- and long-term facilitation, an increase in synaptic strength between sensory neurons and motor neurons thought to underlie behavioural sensitization in the animal. However, few substrates have been identified as candidates that could mediate this increase in synaptic strength. PKMs have been proposed to maintain synaptic strength through preventing endocytosis of AMPA receptors. Numb is a conserved regulator of endocytosis that is modulated by phosphorylation. We have identified and cloned Aplysia Numb (ApNumb). ApNumb contains three conserved PKC phosphorylation sites and PKMs generated from classical and atypical Aplysia PKCs can phosphorylate ApNumb in vitro and in cells. Over-expression of ApNumb that lacks the conserved PKC phosphorylation sites blocks increases in surface levels of a pHluorin-tagged Aplysia glutamate receptor measured using live imaging after intermediate- or long-term facilitation. Over-expression of this form of ApNumb did not block increases in synaptic strength seen during intermediate-term facilitation, but did block increases in synaptic strength seen during long-term facilitation. There was no effect of over-expression of this form ofApNumb on other putative Numb targets as measured using increases in calcium downstream of neurotrophins or agonists of metabotropic glutamate receptors. These results suggest that in Aplysia neurons, Numb specifically regulates AMPA receptor trafficking and is an attractive candidate for a target of PKMs in long-term maintenance of synaptic strength. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.

Action potentials and subthreshold potentials of dorsal horn neurons in a rat model of myositis: a study employing intracellular recordings in vivo.

Intracellular in vivo recordings from rat dorsal horn neurons were made to study the contribution of microglia to the central sensitization of spinal synapses induced by a chronic muscle inflammation. To block microglia activation, minocycline was continuously administered intrathecally during development of the inflammation. The aim was to test whether an inflammation-induced sensitization of dorsal horn neurons is mediated by changes in synaptic strength or other synaptic changes and how activated microglia influence these processes. Intracellular recordings were used to measure subthreshold excitatory postsynaptic potentials (EPSPs) and suprathreshold action potentials (APs). The muscle inflammation significantly increased the proportion of dorsal horn neurons responding with APs or EPSPs to electrical stimulation of the muscle nerve from 27 to 56% (P < 0.01) and to noxious muscle stimulation (3 vs. 44%, P < 0.01). Neurons showing spontaneous ongoing AP or EPSP activity increased from 28 to 74% (P < 0.01). Generally, the increases in suprathreshold AP responses did not occur at the expense of subthreshold EPSPs, because EPSP-only responses also increased. Intrathecal minocycline prevented the inflammation-induced increase in responsiveness to electrical (24%, P < 0.02) and mechanical stimulation (14%, P < 0.02); the effect was stronger on suprathreshold APs than on subthreshold EPSPs. The increase in ongoing activity was only partly suppressed. These data suggest that the myositis-induced hypersensitivity of the dorsal horn neurons to peripheral input and its prevention by intrathecal minocycline treatment were due to both an increase in the number of active synapses and an increased synaptic strength.NEW & NOTEWORTHY During a chronic muscle inflammation (myositis), activated microglia controls both the increase in the number of active synapses and the increase in synaptic strength.

Encephalopathy related to Status Epilepticus during slow Sleep: a link with sleep homeostasis?

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is a childhood epilepsy syndrome characterized by appearance of cognitive and behavioural disturbances in conjunction with a striking activation of EEG epileptic abnormalities during sleep. The link between the extreme amount of epileptic discharges during sleep and the deterioration of cognitive functions and behavior is poorly understood. We hypothesize that the negative effects of ESES may depend on the impairment of the synaptic homeostasis processes occurring during normal sleep and that are particularly important in the developmental age. Sleep ensures synaptic homeostasis by promoting synaptic weakening/elimination after the increase of synaptic strength that occurs during wakefulness. Changes in synaptic strength are reflected in the EEG by changes of sleep slow wave activity (SWA). Recent studies in ESES have failed to show changes of sleep SWA, particularly at the site of the epileptic focus, suggesting a spike-related impairment of the homeostatic recovery of sleep. This impaired synaptic homeostasis in the critical period of development may alter cortical wiring and thereby disrupt, often irreversibly, cognitive functions and behavior, leading to the neuropsychological compromise typical of ESES.

A requirement for epigenetic modifications during noradrenergic stabilization of heterosynaptic LTP in the hippocampus.

Beta-adrenergic receptor (b-AR) activation by noradrenaline (NA) enhances memory formation and long-term potentiation (LTP), a form of synaptic plasticity characterized by an activity-dependent increase in synaptic strength. LTP is believed to be a cellular mechanism for contextual learning and memory. In the mammalian hippocampus, LTP can be observed at multiple synaptic pathways after strong stimulation of a single synaptic pathway. This heterosynaptic LTP is believed to involve synaptic tagging of active synapses and capture of plasticity-related proteins that enable heterosynaptic transfer of persistent potentiation. These processes may permit distinct neural pathways to associate information transmitted by separate, but convergent, synaptic inputs. We had previously shown that transcription and epigenetic modifications were necessary for stabilization of homosynaptic LTP. However, it is unclear whether transfer of LTP to a second, heterosynaptic pathway involves b-ARs signalling to the nucleus. Using electrophysiologic recordings in area CA1 of murine hippocampal slices, we show here that pharmacologically inhibiting b-AR activation, transcription, DNA methyltransferase or histone acetyltransferase activation, prevents stabilization of heterosynaptic LTP. Our data suggest that noradrenergic stabilization of heterosynaptic ("tagged") LTP requires not only transcription, but specifically, DNA methylation and histone acetylation. NA promotes stable heterosynaptic plasticity through engagement of nuclear processes that may contribute to prompt consolidation of short-term memories into resilient long-term memories under conditions when the brain's noradrenergic system is recruited.

Modulation of synaptic plasticity by exercise.

Synaptic plasticity is an experience-dependent process that results in long-lasting changes in synaptic communication. This phenomenon stimulates structural, molecular, and genetic changes in the brain and is the leading biological model for learning and memory processes. Synapses are able to show persistent increases in synaptic strength, or long-term potentiation (LTP), as well as persistent decreases in synaptic strength, known as long-term depression (LTD). Understanding the complex interactions that regulate these activity-dependent processes can provide insight for the development of strategies to improve cognitive function. Twenty years ago, we provided the first evidence indicating that aerobic exercise can reliably enhance LTP, and went on to show that it can also regulate some of the mechanisms involved in LTD induction. Since then, several laboratories have confirmed and expanded these findings, helping to identify different molecular mechanisms involved in exercise-mediated changes in synaptic efficacy. This chapter reviews this material and shows how these experimental findings may prove valuable for alleviating the burden of neurodegenerative diseases in an aging population.

The "Memory" Effect in a Chain of Biochemical Reactions with a Positive Feedback is Enhanced by Substrate Saturation Described by Michaelis-Menten Kinetics.

Information in the brain is stored in a form of an altered synaptic strength between neurons. The long-term potentiation (LTP), a phenomenon when a short-term increase in neural activity is transformed into a long-lasting increase in strengths of synaptic connectivity, provides an experimental substrate of memory. Using reaction-diffusion equations, we established an LTP model, describing the dynamics of glutamate (Glu), calcium (Ca2+) and nitric oxide (NO) in response to the stimulus-a presynaptic action potential. NO can diffuse to the presynaptic terminal and facilitate the Glu release forming a positive feedback loop. Therefore, the LTP can be considered as a chain of biochemical reactions with a positive feedback loop. In this study, we investigated numerically the role of interactions in a chain of biochemical reactions with a positive feedback on the bistable behavior or memory. We conclude that the positive feedback system with the linear interaction between substances does not exhibit a bistable behavior. However, introduction of substrate saturation described by Michaelis-Menten kinetics for NO decay can lead to an increase in synaptic strength lasting for dozens or even hundreds of seconds. Our finding extends a possible role of NO in LTP: a short high intensity stimulus is "memorized" as a long-lasting elevation of NO concentration.

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca2+/CaMKII signaling.

The synapse transmits, processes, and stores data within its tiny space. Effective and specific signaling requires precise alignment of the relevant components. This review examines current insights into mechanisms of AMPAR and NMDAR localization by PSD-95 and their spatial distribution at postsynaptic sites to illuminate the structural and functional framework of postsynaptic signaling. It subsequently delineates how β2 adrenergic receptor (β2 AR) signaling via adenylyl cyclase and the cAMP-dependent protein kinase PKA is organized within nanodomains. Here, we discuss targeting of β2 AR, adenylyl cyclase, and PKA to defined signaling complexes at postsynaptic sites, i.e., AMPARs and the L-type Ca2+ channel Cav1.2, and other subcellular surface localizations, the role of Akinase anchor proteins, the physiological relevance of the spatial restriction of corresponding signaling, and their interplay with signal transduction by the Ca2+- and calmodulin-dependent kinase CaMKII How localized and specific signaling by cAMP occurs is a central cellular question. The dendritic spine constitutes an ideal paradigm for elucidating the dimensions of spatially restricted signaling because of their small size and defined protein composition.

Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

SummaryInformation is encoded in neural networks through changes in synaptic weights. Synaptic learning rules involve a combination of rapid Hebbian plasticity and slower homeostatic synaptic plasticity that regulates neuronal activity through global synaptic scaling. Hebbian and homeostatic plasticity have been extensively investigated, whereas much less is known about their interaction. Here we investigated structural and functional consequences of homeostatic plasticity at dendritic spines of mouse hippocampal neurons. We found that prolonged activity blockade induced spine growth, paralleling synaptic strength increases. Following activity blockade, glutamate uncaging-mediated stimulation at single spines led to size-dependent structural potentiation: smaller spines underwent robust growth, whereas larger spines remained unchanged. Moreover, spines near the stimulated spine exhibited volume changes following homeostatic plasticity, indicating that there was a breakdown of input specificity following homeostatic plasticity. Overall, these findings demonstrate that Hebbian and homeostatic plasticity interact to shape neural connectivity through non-uniform structural plasticity at inputs.

Removal of area CA3 from hippocampal slices induces postsynaptic plasticity at Schaffer collateral synapses that normalizes CA1 pyramidal cell discharge

Neural networks that undergo acute insults display remarkable reorganization. This injury related plasticity is thought to permit recovery of function in the face of damage that cannot be reversed. Previously, an increase in the transmission strength at Schaffer collateral to CA1 pyramidal cell synapses was observed after long-term activity reduction in organotypic hippocampal slices. Here we report that, following acute preparation of adult rat hippocampal slices and surgical removal of area CA3, input to area CA1 was reduced and Schaffer collateral synapses underwent functional strengthening. This increase in synaptic strength was limited to Schaffer collateral inputs (no alteration to temporoammonic synapses) and acted to normalize postsynaptic discharge, supporting a homeostatic or compensatory response. Short-term plasticity was not altered, but an increase in immunohistochemical labeling of GluA1 subunits was observed in the stratum radiatum (but not stratum moleculare), suggesting increased numbers of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and a postsynaptic locus of expression. Combined, these data support the idea that, in response to the reduction in presynaptic activity caused by removal of area CA3, Schaffer collateral synapses undergo a relatively rapid increase in functional efficacy likely supported by insertion of more AMPARs, which maintains postsynaptic excitability in CA1 pyramidal neurons. This novel fast compensatory plasticity exhibits properties that would allow it to maintain optimal network activity levels in the hippocampus, a brain structure lauded for its ongoing experience-dependent malleability.

Regulation and Roles of Autophagy at Synapses.

Genetic studies have demonstrated that conditional ablation of core autophagy genes in the neural lineage leads to progressive neurodegeneration, indicating that this catabolic pathway is indispensable for neuronal maintenance. However, accumulating evidence also indicates that autophagy is not merely a housekeeping process. Instead, autophagy may be dynamically regulated in different neuronal compartments and dictate the turnover of selected cargo in a time- and space-dependent manner and thus contribute to specialized neuronal functions. Here, we review the mechanisms regulating autophagy in neurons and discuss recent findings on the role of autophagy in synaptic morphology and function. Moreover, we discuss relevant questions that remain open and highlight forthcoming issues in the field of neuronal autophagy.

Facilitation of hippocampal long-term potentiation and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking learning, memory, and the potential eradication of HIV-1

Learning and memory are generally considered the behavioral correlates of long-term potentiation (LTP), a form of synaptic plasticity associated with a persistent and long-lasting increase in synaptic strength. Repetitive stimulation of excitatory synapses in the hippocampal CA1 region leads to release and binding of glutamate to the glutamate receptors AMPAR and NMDAR located on pyramidal neurons. Activation of AMPARs facilitates Na+ influx, postsynaptic depolarization, NMDAR-mediated Ca2+ influx, and activation of several intracellular mechanisms that characterize LTP, including increased AMPAR synthesis, ROS production, and ER Ca2+ release. BDNF-TrkB receptor signaling, which increases intracellular Ca2+ levels via PLCγ1-mediated ER Ca2+ release, also plays an important role in facilitating hippocampal CA1 LTP. Interestingly, the cellular mechanisms that characterize LTP are strikingly similar to signaling pathways that underlie reactivation of latent HIV-1 reservoirs. Known as the “shock and kill” approach, reactivation of latent HIV-1, particularly in CD4+ memory T cells, is currently being pursued to potentially eradicate HIV-1. Indeed, AMPARs, NMDARs, and TrkB receptors have been found on and promote T cell activation and BDNF has been shown to reactivate latent HIV-1 in human macrophages. Additionally, latent HIV-1 reactivation via T cell receptor activation (a positive control in HIV-1 latency studies) involves PLCγ1-mediated increases in intracellular Ca2+, an increase in ROS levels, and activation of kinases and transcription factors that are also critical for LTP. Furthermore, PMA, also used as a positive control along with ionomycin in HIV-1 latency studies, has been shown to enhance hippocampal CA1 LTP. AMPK, an evolutionarily conserved kinase activated by increases in intracellular Ca2+, ROS, and/or AMP/ATP ratio increases improves lifespan and healthspan in several model organisms and is essential for T cell activation. Knockdown of AMPK also significantly inhibits HIV-1 replication. AMPK has been found localized in hippocampal CA1 dendrites and glutamate, NMDA, KCl, ionomycin, and BDNF have each been shown to induce AMPK activation in neurons. AMPK activation also increases synthesis and membrane insertion of AMPARs. Because both T cell activation and LTP are dependent on intracellular Ca2+ increases and because inhibition of ROS significantly inhibits hippocampal CA1 LTP and T cell activation, it is our hypothesis that AMPK links latent HIV-1 reactivation with hippocampal LTP, learning, and memory. We also propose that compounds that enhance or promote LTP and reactivate latent HIV-1 (e.g. PMA, ionomycin, resveratrol, metformin, etc.) either alone or in combination likely do so via AMPK activation.

Maternal and Early Postnatal Immune Activation Produce Dissociable Effects on Neurotransmission in mPFC-Amygdala Circuits.

Inflammatory processes may be involved in the pathophysiology of neuropsychiatric illnesses including autism spectrum disorder (ASD). Evidence from studies in rodents indicates that immune activation during early development can produce core features of ASD (social interaction deficits, dysregulation of communication, increases in stereotyped behaviors, and anxiety), although the neural mechanisms of these effects are not thoroughly understood. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, or vehicle on gestational day 12.5 to produce maternal immune activation (MIA). Male offspring received either vehicle or lipopolysaccharide, which simulates a bacterial infection, on postnatal day 9 to produce postnatal immune activation (PIA). We then used optogenetics to address the possibility that early developmental immune activation causes persistent alterations in the flow of signals within the mPFC to basolateral amygdala (BLA) pathway, a circuit implicated in ASD. We found that our MIA regimen produced increases in synaptic strength in glutamatergic projections from the mPFC to the BLA. In contrast, our PIA regimen produced decreases in feedforward GABAergic inhibitory postsynaptic responses resulting from activation of local circuit interneurons in the BLA by mPFC-originating fibers. Both effects were seen together when the regimens were combined. Changes in the balance between excitation and inhibition were differentially translated into the modified spike output of BLA neurons. Our findings raise the possibility that prenatal and postnatal immune activation may affect different cellular targets within brain circuits that regulate some of the core behavioral signs of conditions such as ASD.SIGNIFICANCE STATEMENT Immune system activation during prenatal and early postnatal development may contribute to the development of autism spectrum disorder (ASD). Combining optogenetic approaches and behavioral assays that reflect core features of ASD (anxiety, decreased social interactions), we uncovered mechanisms by which the ASD-associated behavioral impairments induced by immune activation could be mediated at the level of interactions within brain circuits implicated in control of emotion and motivation (mPFC and BLA, specifically). Here, we present evidence that prenatal and postnatal immune activation can have different cellular targets in the brain, providing support to the notion that the etiology of ASD may be linked to the excitation/inhibition imbalance in the brain affecting the signal flow within relevant behavior-driving neural microcircuits.

SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury.

The proper formation and maintenance of functional synapses in the central nervous system (CNS) requires communication between neurons and astrocytes and the ability of astrocytes to release neuromodulatory molecules. Previously, we described a novel role for the astrocyte-secreted matricellular protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) in regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and plasticity at developing synapses. SPARC is highly expressed by astrocytes and microglia during CNS development but its level is reduced in adulthood. Interestingly, SPARC has been shown to be upregulated in CNS injury and disease. However, the role of SPARC upregulation in these contexts is not fully understood. In this study, we investigated the effect of chronic SPARC administration on glutamate receptors on mature hippocampal neuron cultures and following CNS injury. We found that SPARC treatment increased the number of GluA1-containing AMPARs at synapses and enhanced synaptic function. Furthermore, we determined that the increase in synaptic strength induced by SPARC could be inhibited by Philanthotoxin-433, a blocker of homomeric GluA1-containing AMPARs. We then investigated the effect of SPARC treatment on neuronal health in an injury context where SPARC expression is upregulated. We found that SPARC levels are increased in astrocytes and microglia following middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Remarkably, chronic pre-treatment with SPARC prevented OGD-induced loss of synaptic GluA1. Furthermore, SPARC treatment reduced neuronal death through Philanthotoxin-433 sensitive GluA1 receptors. Taken together, this study suggests a novel role for SPARC and GluA1 in promoting neuronal health and recovery following CNS damage.

CJun N-terminal kinase (JNK) mediates cortico-striatal signaling in a model of Parkinson's disease

The cJun N-terminal kinase (JNK) signaling pathway has been extensively studied with regard to its involvement in neurodegenerative processes, but little is known about its functions in neurotransmission. In a mouse model of Parkinson's disease (PD), we show that the pharmacological activation of dopamine D1 receptors (D1R) produces a large increase in JNK phosphorylation. This effect is secondary to dopamine depletion, and is restricted to the striatal projection neurons that innervate directly the output structures of the basal ganglia (dSPN). Activation of JNK in dSPN relies on cAMP-induced phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32), but does not require N-methyl-d-aspartate (NMDA) receptor transmission. Electrophysiological experiments on acute brain slices from PD mice show that inhibition of JNK signaling in dSPN prevents the increase in synaptic strength caused by activation of D1Rs. Together, our findings show that dopamine depletion confers to JNK the ability to mediate dopamine transmission, informing the future development of therapies for PD.

Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis

AimsBoth N-type and P/Q-type voltage-gated Ca2+ channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). Main methods(S)-3,5-Dihydroxyphenylglycine (DHPG; 10μM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. Key findingsWeak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20−40% of Ca2+ currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca2+ currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. SignificanceOur data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo.

Loss of Doc2-Dependent Spontaneous Neurotransmission Augments Glutamatergic Synaptic Strength

Action potential-evoked vesicle fusion comprises the majority of neurotransmission within chemical synapses, but action potential-independent spontaneous neurotransmission also contributes to the collection of signals sent to the postsynaptic cell. Previous work has implicated spontaneous neurotransmission in homeostatic synaptic scaling, but few studies have selectively manipulated spontaneous neurotransmission without substantial changes in evoked neurotransmission to study this function in detail. Here we used a quadruple knockdown strategy to reduce levels of proteins within the soluble calcium-binding double C2 domain (Doc2)-like protein family to selectively reduce spontaneous neurotransmission in cultured mouse and rat neurons. Activity-evoked responses appear normal while both excitatory and inhibitory spontaneous events exhibit reduced frequency. Excitatory miniature postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), increase in amplitude after quadruple knockdown. This increase in synaptic efficacy correlates with reduced phosphorylation levels of eukaryotic elongation factor 2 and also requires the presence of elongation factor 2 kinase. Together, these data suggest that spontaneous neurotransmission independently contributes to the regulation of synaptic efficacy, and action potential-evoked and spontaneous neurotransmission can be segregated at least partially on a molecular level.SIGNIFICANCE STATEMENT Action potential-evoked and spontaneous neurotransmission have been observed in nervous system circuits as long as methods have existed to measure them. Despite being well studied, controversy still remains about whether these forms of neurotransmission are regulated independently on a molecular level or whether they are simply a continuum of neurotransmission modes. In this study, members of the Doc2 family of presynaptic proteins were eliminated, which caused a reduction in spontaneous neurotransmission, whereas action potential-evoked neurotransmission remained relatively normal. This protein loss also caused an increase in synaptic strength, suggesting that spontaneous neurotransmission is able to communicate independently with the postsynaptic neuron and trigger downstream signaling cascades that regulate the synaptic state.

An Intrinsic Transcriptional Program Underlying Synaptic Scaling during Activity Suppression

Homeostatic scaling allows neurons to maintain stable activity patterns by globally altering their synaptic strength in response to changing activity levels. Suppression of activity by the blocking of action potentials increases synaptic strength through anupregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Although this synaptic upscaling was shown to require transcription, the molecular nature of the intrinsic transcription program underlying this process and its functional significance have been unclear. Using RNA-seq, we identified 73 genes that were specifically upregulated in response to activity suppression. In particular, Neuronal pentraxin-1 (Nptx1) increased within 6hr of activity blockade, and knockdown of this gene blocked the increase in synaptic strength. Nptx1 induction is mediated by calcium influx through the T-type voltage-gated calcium channel, as well as two transcription factors, SRF and ELK1. Altogether, these results uncover a transcriptional program that specifically operates when neuronal activity is suppressed to globally coordinate the increase in synaptic strength.

Accumbens nNOS Interneurons Regulate Cocaine Relapse.

Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus accumbens. We demonstrate the sequence of events that mediates synaptic potentiation and reinstated cocaine seeking induced by cocaine-conditioned cues. Activation of prefrontal inputs to the accumbens by cues initiates spillover of synaptic glutamate, which stimulates metabotropic glutamate receptor 5 (mGluR5) on a small population of interneurons (∼1%) expressing neuronal nitric oxide synthase. Stimulating these glutamate receptors increases nitric oxide (NO) production, which stimulates matrix metalloprotease-2 (MMP-2) and MMP-9 activity in the extracellular space. Manipulating the interaction between mGluR5, NO production, or MMP-2 and MMP-9 pharmacologically or genetically is sufficient to recapitulate transient synaptic potentiation and reinstate cocaine seeking.

Modeling of synchronization behavior of bursting neurons at nonlinearly coupled dynamical networks

ABSTRACTSynchronization behaviors of bursting neurons coupled through electrical and dynamic chemical synapses are investigated. The Izhikevich model is used with random and small world network of bursting neurons. Various currents which consist of diffusive electrical and time-delayed dynamic chemical synapses are used in the simulations to investigate the influences of synaptic currents and couplings on synchronization behavior of bursting neurons. The effects of parameters, such as time delay, inhibitory synaptic strengths, and decay time on synchronization behavior are investigated. It is observed that in random networks with no delay, bursting synchrony is established with the electrical synapse alone, single spiking synchrony is observed with hybrid coupling. In small world network with no delay, periodic bursting behavior with multiple spikes is observed when only chemical and only electrical synapse exist. Single-spike and multiple-spike bursting are established with hybrid couplings. A decrease in the synchronization measure is observed with zero time delay, as the decay time is increased in random network. For synaptic delays which are above active phase period, synchronization measure increases with an increase in synaptic strength and time delay in small world network. However, in random network, it increases with only an increase in synaptic strength.