Timing-dependent Long-term Potentiation Research Articles

Differential vulnerability of hippocampal CA3-CA1 synapses to A\u03b2

Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt−/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aβ1–42 (hAβ) in wild-type (WT) mice, but not in tau-knockout (Mapt−/−) mice. We then tested whether NMDAR currents were affected by hAβ; we found that hAβ reduced the postsynaptic NMDAR current in WT mice but not in Mapt−/− mice, while the NMDAR current was reduced to a similar extent by the GluN2B-selective NMDAR antagonist Ro 25–6981. To further investigate a possible difference in GluN2B-containing NMDARs in Mapt−/− mice, we used optogenetics to compare NMDAR/AMPAR ratio of EPSCs in CA1 synapses with input from left vs right CA3. It was previously reported in WT mice that hippocampal synapses in CA1 that receive input from the left CA3 display a higher NMDAR charge transfer and a higher Ro-sensitivity than synapses in CA1 that receive input from the right CA3. Here we observed the same pattern in Mapt−/− mice, thus differential NMDAR subunit expression does not explain the difference in hAβ effect on LTP. Finally, we asked whether synapses with left vs right CA3 input are differentially affected by hAβ in WT mice. We found that NMDAR current in synapses with input from the left CA3 were reduced while synapses with input from the right CA3 were unaffected by acute hAβ exposure. These results suggest that hippocampal CA3-CA1 synapses with presynaptic axon originating in the left CA3 are selectively vulnerable to Aβ and that a genetic knock out of tau protein protects them from Aβ synaptotoxicity.

Calcium-Permeable AMPA Receptors Mediate Timing-Dependent LTP Elicited by Low Repeat Coincident Pre- and Postsynaptic Activity at Schaffer Collateral-CA1 Synapses.

High-frequency stimulation induced long-term potentiation (LTP) and low-frequency stimulation induced LTD are considered as cellular models of memory formation. Interestingly, spike timing-dependent plasticity (STDP) can induce equally robust timing-dependent LTP (t-LTP) and t-LTD in response to low frequency repeats of coincident action potential (AP) firing in presynaptic and postsynaptic cells. Commonly, STDP paradigms relying on 25-100 repeats of coincident AP firing are used to elicit t-LTP or t-LTD, but the minimum number of repeats required for successful STDP is barely explored. However, systematic investigation of physiologically relevant low repeat STDP paradigms is of utmost importance to explain learning mechanisms in vivo. Here, we examined low repeat STDP at Schaffer collateral-CA1 synapses by pairing one presynaptic AP with either one postsynaptic AP (1:1t-LTP), or a burst of 4 APs (1:4t-LTP) and found 3-6 repeats to be sufficient to elicit t-LTP. 6× 1:1t-LTP required postsynaptic Ca2+ influx via NMDARs and L-type VGCCs and was mediated by increased presynaptic glutamate release. In contrast, 1:4t-LTP depended on postsynaptic metabotropic GluRs and ryanodine receptor signaling and was mediated by postsynaptic insertion of AMPA receptors. Unexpectedly, both 6× t-LTP variants were strictly dependent on activation of postsynaptic Ca2+-permeable AMPARs but were differentially regulated by dopamine receptor signaling. Our data show that synaptic changes induced by only 3-6 repeats of mild STDP stimulation occurring in ≤10s can take place on time scales observed also during single trial learning.

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+ currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β-Kv4.2 axis may be an attractive therapeutic target for MDD.

Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent\xa0long-term potentiation impaired by amyloid \u03b2 oligomers

BackgroundAbnormal accumulation of amyloid β1–42 oligomers (AβO1–42), a hallmark of Alzheimer’s disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AβO1–42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AβO1–42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP.ResultsTargeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AβO1–42 causes synapse-specific dysfunction in PV and SST interneurons. AβO1–42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AβO1–42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AβO1–42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction.ConclusionsOur results reveal that AβO1–42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer’s disease.

Neonatal Injury Alters Sensory Input and Synaptic Plasticity in GABAergic Interneurons of the Adult Mouse Dorsal Horn.

Neonatal tissue injury disrupts the balance between primary afferent-evoked excitation and inhibition onto adult spinal projection neurons. However, whether this reflects cell-type-specific alterations at synapses onto ascending projection neurons, or rather is indicative of global changes in synaptic signaling across the mature superficial dorsal horn (SDH), remains unknown. Therefore the present study investigated the effects of neonatal surgical injury on primary afferent synaptic input to adult mouse SDH interneurons using in vitro patch-clamp techniques. Hindpaw incision at postnatal day (P)3 significantly diminished total primary afferent-evoked glutamatergic drive to adult Gad67-GFP and non-GFP neurons, and reduced their firing in response to sensory input, in both males and females. Early tissue damage also shaped the relative prevalence of monosynaptic A- versus C-fiber-mediated input to mature GABAergic neurons, with an increased prevalence of Aβ- and Aδ-fiber input observed in neonatally-incised mice compared with naive littermate controls. Paired presynaptic and postsynaptic stimulation at an interval that exclusively produced spike timing-dependent long-term potentiation (t-LTP) in projection neurons predominantly evoked NMDAR-dependent long-term depression in naive Gad67-GFP interneurons. Meanwhile, P3 tissue damage enhanced the likelihood of t-LTP generation at sensory synapses onto the mature GABAergic population, and increased the contribution of Ca2+-permeable AMPARs to the overall glutamatergic response. Collectively, the results indicate that neonatal injury suppresses sensory drive to multiple subpopulations of interneurons in the adult SDH, which likely represents one mechanism contributing to reduced feedforward inhibition of ascending projection neurons, and the priming of developing pain pathways, following early life trauma.SIGNIFICANCE STATEMENT Mounting clinical and preclinical evidence suggests that neonatal tissue damage can result in long-term changes in nociceptive processing within the CNS. Although recent work has demonstrated that early life injury weakens the ability of sensory afferents to evoke feedforward inhibition of adult spinal projection neurons, the underlying circuit mechanisms remain poorly understood. Here we demonstrate that neonatal surgical injury leads to persistent deficits in primary afferent drive to both GABAergic and presumed glutamatergic neurons in the mature superficial dorsal horn (SDH), and modifies activity-dependent plasticity at sensory synapses onto the GABAergic population. The functional denervation of spinal interneurons within the mature SDH may contribute to the "priming" of developing pain pathways following early life injury.

A kinetic model for Brain-Derived Neurotrophic Factor mediated spike timing-dependent LTP.

Across the mammalian nervous system, neurotrophins control synaptic plasticity, neuromodulation, and neuronal growth. The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is known to promote structural and functional synaptic plasticity in the hippocampus, the cerebral cortex, and many other brain areas. In recent years, a wealth of data has been accumulated revealing the paramount importance of BDNF for neuronal function. BDNF signaling gives rise to multiple complex signaling pathways that mediate neuronal survival and differentiation during development, and formation of new memories. These different roles of BDNF for neuronal function have essential consequences if BDNF signaling in the brain is reduced. Thus, BDNF knock-out mice or mice that are deficient in BDNF receptor signaling via TrkB and p75 receptors show deficits in neuronal development, synaptic plasticity, and memory formation. Accordingly, BDNF signaling dysfunctions are associated with many neurological and neurodegenerative conditions including Alzheimer’s and Huntington’s disease. However, despite the widespread implications of BDNF-dependent signaling in synaptic plasticity in healthy and pathological conditions, the interplay of the involved different biochemical pathways at the synaptic level remained mostly unknown. In this paper, we investigated the role of BDNF/TrkB signaling in spike-timing dependent plasticity (STDP) in rodent hippocampus CA1 pyramidal cells, by implementing the first subcellular model of BDNF regulated, spike timing-dependent long-term potentiation (t-LTP). The model is based on previously published experimental findings on STDP and accounts for the observed magnitude, time course, stimulation pattern and BDNF-dependence of t-LTP. It allows interpreting the main experimental findings concerning specific biomolecular processes, and it can be expanded to take into account more detailed biochemical reactions. The results point out a few predictions on how to enhance LTP induction in such a way to rescue or improve cognitive functions under pathological conditions.

Prostaglandin Signaling Governs Spike Timing-Dependent Plasticity at Sensory Synapses onto Mouse Spinal Projection Neurons.

Highly correlated presynaptic and postsynaptic activity evokes spike timing-dependent long-term potentiation (t-LTP) at primary afferent synapses onto spinal projection neurons. While prior evidence indicates that t-LTP depends upon an elevation in intracellular Ca2+ within projection neurons, the downstream signaling pathways that trigger the observed increase in glutamate release from sensory neurons remain poorly understood. Using in vitro patch-clamp recordings from female mouse lamina I spino-parabrachial neurons, the present study demonstrates a critical role for prostaglandin synthesis in the generation of t-LTP. Bath application of the selective phospholipase A2 (PLA2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) or the cyclooxygenase 2 (Cox-2) inhibitor nimesulide prevented t-LTP at sensory synapses onto spino-parabrachial neurons. Similar results were observed following the block of the EP2 subtype of prostaglandin E2 (PGE2) receptor with PF 04418948. Meanwhile, perfusion with PGE2 or the EP2 agonist butaprost potentiated the amplitude of monosynaptic primary afferent-evoked EPSCs while decreasing the paired-pulse ratio, suggesting a presynaptic site of action. Cox-2 was constitutively expressed in both spinal microglia and lamina I projection neurons within the superficial dorsal horn (SDH). Suppression of microglial activation with minocycline had no effect on the production of t-LTP, suggesting the possibility that prostaglandins produced within projection neurons could contribute to an enhanced probability of glutamate release at primary afferent synapses. Collectively, the results suggest that the amplification of ascending nociceptive transmission by the spinal SDH network is governed by PLA2-Cox-2-PGE2 signaling.SIGNIFICANCE STATEMENT Long-term potentiation (LTP) of primary afferent synapses contributes to the sensitization of spinal nociceptive circuits and has been linked to greater pain sensation in humans. Prior work has implicated elevated glutamate release in the generation of spike timing-dependent LTP (t-LTP) at sensory synapses onto ascending spinal projection neurons, but the underlying mechanisms remain unknown. Here we provide evidence that the activation of EP2 prostaglandin receptors by prostaglandin E2, occurring downstream of phospholipase A2 and cyclooxygenase 2 activation, mediates t-LTP at these synapses via changes in presynaptic function. This suggests that prostaglandins can increase the flow of nociceptive information from the spinal cord to the brain independently of their known ability to suppress synaptic inhibition within the dorsal horn.

P.1.g.043 - Aβ1-42 impairs mGluR5-gated spike timing-dependent long-term potentiation by disrupting CB1 receptors

P.1.g.043 - Aβ1-42 impairs mGluR5-gated spike timing-dependent long-term potentiation by disrupting CB1 receptors

Timing-dependent LTP and LTD in mouse primary visual cortex following different visual deprivation models.

Visual deprivation during the critical period induces long-lasting changes in cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity at synapses. Spike timing-dependent plasticity (STDP) is considered a strong candidate for experience-dependent changes. However, the visual deprivation forms that affect timing-dependent long-term potentiation(LTP) and long-term depression(LTD) remain unclear. Here, we demonstrated the temporal window changes of tLTP and tLTD, elicited by coincidental pre- and post-synaptic firing, following different modes of 6-day visual deprivation. Markedly broader temporal windows were found in robust tLTP and tLTD in the V1M of the deprived visual cortex in mice after 6-day MD and DE. The underlying mechanism for the changes seen with visual deprivation in juvenile mice using 6 days of dark exposure or monocular lid suture involves an increased fraction of NR2b-containing NMDAR and the consequent prolongation of NMDAR-mediated response duration. Moreover, a decrease in NR2A protein expression at the synapse is attributable to the reduction of the NR2A/2B ratio in the deprived cortex.

Dopamine Receptors Differentially Control Binge Alcohol Drinking-Mediated Synaptic Plasticity of the Core Nucleus Accumbens Direct and Indirect Pathways.

Binge alcohol drinking, a behavior characterized by rapid repeated alcohol intake, is most prevalent in young adults and is a risk factor for excessive alcohol consumption and alcohol dependence. Although the alteration of synaptic plasticity is thought to contribute to this behavior, there is currently little evidence that this is the case. We used drinking in the dark (DID) as a model of binge alcohol drinking to assess its effects on spike timing-dependent plasticity (STDP) in medium spiny neurons (MSNs) of the core nucleus accumbens (NAc) by combining patch-clamp recordings with calcium imaging and optogenetics. After 2 weeks of daily alcohol binges, synaptic plasticity was profoundly altered. STDP in MSNs expressing dopamine D1 receptors shifted from spike-timing-dependent long-term depression (tLTD), the predominant form of plasticity in naive male mice, to spike-timing-dependent long-term potentiation (tLTP) in DID mice, an effect that was totally reversed in the presence of 4 μm SCH23390, a dopamine D1 receptor antagonist. In MSNs presumably expressing dopamine D2 receptors, tLTP, the main form of plasticity in naive mice, was inhibited in DID mice. Interestingly, 1 μm sulpiride, a D2 receptor antagonist, restored tLTP. Although we observed no alterations of AMPA and NMDA receptor properties, we found that the AMPA/NMDA ratio increased at cortical and amygdaloid inputs but not at hippocampal inputs. Also, DID effects on STDP were accompanied by lower dendritic calcium transients. These data suggest that the role of dopamine in mediating the effects of binge alcohol drinking on synaptic plasticity of NAc MSNs differs markedly whether these neurons belong to the direct or indirect pathways.SIGNIFICANCE STATEMENT We examined the relationship between binge alcohol drinking and spike timing-dependent plasticity in nucleus accumbens (NAc) neurons. We found that repeated drinking bouts modulate differently synaptic plasticity in medium spiny neurons of the accumbens direct and indirect pathways. While timing-dependent long-term depression switches to long-term potentiation (LTP) in the former, timing-dependent LTP is inhibited in the latter. These effects are not accompanied by changes in AMPA and NMDA receptor properties at cortical, amygdaloid, and hippocampal synapses. Interestingly, dopamine D1 and D2 receptor antagonists have opposite effects on plasticity. Our data show that whether core NAc medium spiny neurons belong to the direct or indirect pathways determines the form of spike timing-dependent plasticity (STDP), the manner by which STDP responds to binge alcohol drinking, and its sensitivity to dopamine receptor antagonists.

Hebbian Spike-Timing Dependent Plasticity at the Cerebellar Input Stage.

Spike-timing-dependent plasticity (STDP) is a form of long-term synaptic plasticity exploiting the time relationship between postsynaptic action potentials (APs) and EPSPs. Surprisingly enough, very little was known about STDP in the cerebellum, although it is thought to play a critical role for learning appropriate timing of actions. We speculated that low-frequency oscillations observed in the granular layer may provide a reference for repetitive EPSP/AP phase coupling. Here we show that EPSP-spike pairing at 6 Hz can optimally induce STDP at the mossy fiber-granule cell synapse in rats. Spike timing-dependent long-term potentiation and depression (st-LTP and st-LTD) were confined to a ±25 ms time-window. Because EPSPs led APs in st-LTP while APs led EPSPs in st-LTD, STDP was Hebbian in nature. STDP occurred at 6-10 Hz but vanished >50 Hz or <1 Hz (where only LTP or LTD occurred). STDP disappeared with randomized EPSP/AP pairing or high intracellular Ca2+ buffering, and its sign was inverted by GABA-A receptor activation. Both st-LTP and st-LTD required NMDA receptors, but st-LTP also required reinforcing signals mediated by mGluRs and intracellular calcium stores. Importantly, st-LTP and st-LTD were significantly larger than LTP and LTD obtained by modulating the frequency and duration of mossy fiber bursts, probably because STDP expression involved postsynaptic in addition to presynaptic mechanisms. These results thus show that a Hebbian form of STDP occurs at the cerebellum input stage, providing the substrate for phase-dependent binding of mossy fiber spikes to repetitive theta-frequency cycles of granule cell activity.SIGNIFICANCE STATEMENT Long-term synaptic plasticity is a fundamental property of the brain, causing persistent modifications of neuronal communication thought to provide the cellular basis of learning and memory. The cerebellum is critical for learning the appropriate timing of sensorimotor behaviors, but whether and how appropriate spike patterns could drive long-term synaptic plasticity remained unknown. Here, we show that this can actually occur through a form of spike-timing-dependent plasticity (STDP) at the cerebellar inputs stage. Pairing presynaptic and postsynaptic spikes at 6-10 Hz reliably induced STDP at the mossy fiber-granule cell synapse, with potentiation and depression symmetrically distributed within a ±25 ms time window. Thus, STDP can bind plasticity to the mossy fiber burst phase with high temporal precision.

Functional Organization of Cutaneous and Muscle Afferent Synapses onto Immature Spinal Lamina I Projection Neurons.

It is well established that sensory afferents innervating muscle are more effective at inducing hyperexcitability within spinal cord circuits compared with skin afferents, which likely contributes to the higher prevalence of chronic musculoskeletal pain compared with pain of cutaneous origin. However, the mechanisms underlying these differences in central nociceptive signaling remain incompletely understood, as nothing is known about how superficial dorsal horn neurons process sensory input from muscle versus skin at the synaptic level. Using a novel ex vivo spinal cord preparation, here we identify the functional organization of muscle and cutaneous afferent synapses onto immature rat lamina I spino-parabrachial neurons, which serve as a major source of nociceptive transmission to the brain. Stimulation of the gastrocnemius nerve and sural nerve revealed significant convergence of muscle and cutaneous afferent synaptic input onto individual projection neurons. Muscle afferents displayed a higher probability of glutamate release, although short-term synaptic plasticity was similar between the groups. Importantly, muscle afferent synapses exhibited greater relative expression of Ca2+-permeable AMPARs compared with cutaneous inputs. In addition, the prevalence and magnitude of spike timing-dependent long-term potentiation were significantly higher at muscle afferent synapses, where it required Ca2+-permeable AMPAR activation. Collectively, these results provide the first evidence for afferent-specific properties of glutamatergic transmission within the superficial dorsal horn. A larger propensity for activity-dependent strengthening at muscle afferent synapses onto developing spinal projection neurons could contribute to the enhanced ability of these sensory inputs to sensitize central nociceptive networks and thereby evoke persistent pain in children following injury.SIGNIFICANCE STATEMENT The neurobiological mechanisms underlying the high prevalence of chronic musculoskeletal pain remain poorly understood, in part because little is known about why sensory neurons innervating muscle appear more capable of sensitizing nociceptive pathways in the CNS compared with skin afferents. The present study identifies, for the first time, the functional properties of muscle and cutaneous afferent synapses onto immature lamina I projection neurons, which convey nociceptive information to the brain. Despite many similarities, an enhanced relative expression of Ca2+-permeable AMPA receptors at muscle afferent synapses drives greater LTP following repetitive stimulation. A preferential ability of the dorsal horn synaptic network to amplify nociceptive input arising from muscle is predicted to favor the generation of musculoskeletal pain following injury.

Developmental Switch in Spike Timing-Dependent Plasticity and Cannabinoid-Dependent Reorganization of the Thalamocortical Projection in the Barrel Cortex.

The formation and refinement of thalamocortical axons (TCAs) is an activity-dependent process (Katz and Shatz, 1996), but its mechanism and nature of activity are elusive. We studied the role of spike timing-dependent plasticity (STDP) in TCA formation and refinement in mice. At birth (postnatal day 0, P0), TCAs invade the cortical plate, from which layers 4 (L4) and L2/3 differentiate at P3-P4. A portion of TCAs transiently reach toward the pia surface around P2-P4 (Senft and Woolsey, 1991; Rebsam et al., 2002) but are eventually confined below the border between L2/3 and L4. We previously showed that L4-L2/3 synapses exhibit STDP with only potentiation (timing-dependent long-term potentiation [t-LTP]) during synapse formation, then switch to a Hebbian form of STDP. Here we show that TCA-cortical plate synapses exhibit robust t-LTP in neonates, whose magnitude decreased gradually after P4-P5. After L2/3 is differentiated, TCA-L2/3 gradually switched to STDP with only depression (t-LTD) after P7-P8, whereas TCA-L4 lost STDP. t-LTP was dependent on NMDA receptor and PKA, whereas t-LTD was mediated by Type 1 cannabinoid receptors (CB1Rs) probably located at TCA terminals, revealed by global and cortical excitatory cell-specific knock-out of CB1R. Moreover, we found that administration of CB1R agonists, including Δ(9)-tetrahydrocannabinol, caused substantial retraction of TCAs. Consistent with this, individual thalamocortical axons exuberantly innervated L2/3 at P12 in CB1R knock-outs, indicating that endogenous cannabinoid signaling shapes TCA projection. These results suggest that the developmental switch in STDP and associated appearance of CB1R play important roles in the formation and refinement of TCAs. It has been shown that neural activity is required for initial synapse formation of thalamocortical axons with cortical cells, but precisely what sort of activities in presynaptic and postsynaptic cells are required is not yet clear. In addition, how activity is further translated into structural changes is unclear. We show here that the period during which spike timing-dependent long-term potentiation and depression (t-LTP, t-LTD) can be induced closely matches the time course of synapse formation and retraction, respectively, at the thalamocortical synapse. Moreover, administration of cannabinoid agonists, which mimic t-LTD, caused TCA retraction, suggesting that cannabinoids translate physiological changes into morphological consequences.

Presynaptic Spike Timing-Dependent Long-Term Depression in the Mouse Hippocampus.

Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12–P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca2+ for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca2+ release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.

Dopamine-enabled anti-Hebbian timing-dependent plasticity in prefrontal circuitry.

Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre–post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post–pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post–pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post–pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.

Developmental Switch in Spike Timing-Dependent Plasticity at Layers 4–2/3 in the Rodent Barrel Cortex

Sensory deprivation during the critical period induces long-lasting changes in cortical maps. In the rodent somatosensory cortex (S1), its precise initiation mechanism is not known, yet spike timing-dependent plasticity (STDP) at layer 4 (L4)-L2/3 synapses are thought to be crucial. Whisker stimulation causes "L4 followed by L2/3" cell firings, while acute single whisker deprivation suddenly reverses the sequential order in L4 and L2/3 neurons in the deprived column (Celikel et al., 2004). Reversed spike sequence then leads to long-term depression through an STDP mechanism (timing-dependent long-term depression), known as deprivation-induced suppression at L4-L2/3 synapses (Bender et al., 2006a), an important first step in the map reorganization. Here we show that STDP properties change dramatically on postnatal day 13-15 (P13-P15) in mice S1. Before P13, timing-dependent long-term potentiation (t-LTP) was predominantly induced regardless of spiking order. The induction of t-LTP required postsynaptic influx of Ca(2+), an activation of protein kinase A, but not calcium/calmodulin-dependent protein kinase II. Consistent with the strong bias toward t-LTP, whisker deprivation (all whiskers in Row "D") from P7-P12 failed to induce synaptic depression at L4-L2/3 synapses in the deprived column, but clear depression was seen if deprivation occurred after P14. Random activation of L4, L2/3 cells, as may occur in response to whisker stimulation before P13 during network formation, led to potentiation under the immature STDP rule, as predicted from the bias toward t-LTP regardless of spiking order. These findings describe a developmental switch in the STDP rule that may underlie the transition from synapse formation to circuit reorganization at L4-L2/3 synapses, both in distinct activity-dependent manners.

AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors

It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit-impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing-dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors.

Gating of NMDA receptor-mediated hippocampal spike timing-dependent potentiation by mGluR5

Hippocampal long-term potentiation (LTP) is believed to be important for learning and memory. Experimentally, the pairing of precisely timed pre- and postsynaptic spikes within a time window of ∼10 ms can induce timing-dependent LTP (tLTP), but the requirements for induction of tLTP change with development: in young rodents single postsynaptic spikes are sufficient to induce tLTP, whereas postsynaptic burst firing appears to be required in the adult. However, hippocampal neurons in vivo show theta-modulated single spike activities also in older hippocampus. Here we investigated the conditions for single spike pairing to induce tLTP at older CA3–CA1 synapses. We found that the pairing of single pre- and postsynaptic spikes could induce tLTP in older hippocampus when the postsynaptic neuronal membrane was depolarized and the pairing frequency exceeded ∼4 Hz. The spike frequency requirement is postsynaptic, as tLTP could still be induced with presynaptic stimulation at 1 Hz as long as the postsynaptic spike frequency exceeded ∼4 Hz, suggesting that postsynaptic theta-frequency activity is required for the successful induction of tLTP at older CA3–CA1 synapses. The induction of tLTP was blocked by an NMDA receptor antagonist and by the selective mGluR5 blockers, MPEP and MTEP, whereas activation of mGluR1 and mGluR5 by DHPG relieved the postsynaptic spike frequency requirement for tLTP induction. These results suggest that activation of mGluR5 during single-spike pairing at older CA3–CA1 synapses gates NMDA receptor-dependent tLTP.

Protein Kinase Mζ Is Necessary for Cocaine-Induced Synaptic Potentiation in the Ventral Tegmental Area

Much progress has been made in our understanding of brain regions and specific receptors that are involved in the action of cocaine addiction. Although long-term modifications of mesolimbic reward circuit following cocaine exposure are responsible for cocaine-addicted behaviors, the underlying molecular mechanism at the cellular level is still obscure. Here, we investigated the possible participation of protein kinase Mζ (PKMζ) in synaptic potentiation following cocaine exposure. Spontaneous and evoked synaptic activity of glutamate synapse in saline- and cocaine-treated rats were examined by preparing acute brain slices and performing whole-cell voltage-clamp recordings from individual dopamine neurons in the ventral tegmental area (VTA). We also assessed the role of PKMζ on the behavioral responses by cocaine conditioned place preference. Chelerythrine, an inhibitor of PKMζ, reversed the cocaine-induced facilitation of spontaneous synaptic transmission in the VTA. PKMζ inhibition by chelerythrine or myristoylated ζ inhibitory peptide significantly attenuated the cocaine exposure-induced enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio. Myristoylated ζ inhibitory peptide had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKMζ level. Furthermore, intracranial infusion of myristoylated ζ inhibitory peptide in the VTA disrupted cocaine conditioned place preference. Our results suggest that persistent activity of PKMζ is a requisite for cocaine-induced enhancement of synaptic plasticity in the VTA and cocaine conditioned place preference.

Spike‐timing‐dependent plasticity in hippocampal CA3 neurons

Synaptic plasticity of different inputs converging onto CA3 pyramidal neurons is central to theories of hippocampal function. The mossy fibre (MF) input to these neurons is thought to exhibit plasticity that is in nearly all aspects fundamentally different from plasticity in other brain regions: in particular, when induced by high frequency presynaptic stimulation, plasticity at these synapses is independent of NMDA receptor (NMDAR) activation and presynaptically expressed. Here, we show that different stimulation protocols that depend on the close timing of MF activity and postsynaptic spikes induce bidirectional plasticity in CA3 neurons in 3-week-old rats. Long-term potentiation (LTP) is observed when an excitatory postsynaptic potential (EPSP), evoked by MF stimulation, precedes a single postsynaptic action potential (AP) or a brief AP burst by 10 ms. Instead, timing-dependent long-term depression (LTD) requires the pairing of a single AP to an EPSP with a delay of 30 ms. The pairing of APs to synaptic activity is required for plasticity induction, since the application of unpaired APs or EPSPs did not alter synaptic strength. Furthermore, our results demonstrate that both timing-dependent LTP and LTD critically depend on the activation of NMDARs. Specifically blocking postsynaptic NMDARs prevents plasticity, demonstrating that NMDARs important to spike-timing-dependent plasticity in CA3 neurons are required at postsynaptic sites. In summary, this study shows that the close timing of APs to MF excitatory synaptic input can alter synaptic efficacy in CA3 neurons in a bidirectional manner.