Persistent synaptic activity produces long-lasting enhancement of endocannabinoid modulation and alters long-term synaptic plasticity

Learning and memory are thought to involve activity-dependent changes in synaptic efficacy such as long-term potentiation (LTP) and long-term depression (LTD). Recent studies have indicated that endocannabinoid-dependent modulation of inhibitory transmission facilitates induction of hippocampal LTP and that endocannabinoids play a key role in certain forms of LTD. Here, we show that repetitive low-frequency synaptic stimulation (LFS) produces persistent up-regulation of endocannabinoid signaling at hippocampal CA1 GABAergic synapses. This LFS also produces LTD of inhibitory synapses and facilitates LTP at excitatory, glutamatergic synapses. These endocannabinoid-mediated plastic changes could contribute to information storage within the brain.     

Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.     

A beta 25-35-induced depression of long-term potentiation in area CA1 in vivo and in vitro is attenuated by verapamil

The effect of intracerebroventricular (icv) injection of A beta 25-35 and/or intraperitoneal (ip) application of the L-type calcium channel (VDCC) blockers verapamil or diltiazem were examined in vivo. To by-pass possible systemic actions of these agents, their effects on long-term potentiation (LTP) in the CA1 region of the in vitro hippocampal slice preparation were also examined. Application of A beta 25-35 (10 nmol in 5 microl, i.c.v.) significantly impaired LTP in vivo, as did IP injection of verapamil (1 or 10 mg/kg) or diltiazem (1 or 10 mg/kg). In the in vitro slice preparation, LTP was also depressed by prior application of A beta 25-35 (500 nmol), verapamil (20 microM), or diltiazem (50 microM). Combined application of A beta 25-35 and verapamil in either the in vivo or in vitro preparation resulted in a significant reversal of the LTP depression observed in the presence of either agent alone. However, co-application of diltiazem and A beta 25-35 failed to attenuate the depression of LTP observed in the presence of either agent alone in vivo or in vitro. Since LTP is a cellular correlate of memory and A beta is known to be involved in Alzheimer's disease (AD), these results indicate that verapamil, a phenylalkylamine, may be useful in the treatment of cognitive deficits associated with AD.     

Adenosine acting on A1 receptors protects NO-triggered rebound potentiation and LTP in rat hippocampal slices

Exposure of hippocampal slices to nitric oxide (NO) results in a depression of CA1 synaptic transmission. Under 0.2-Hz stimulation, washout of NO leads to a persistent potentiation that depends on N-methyl-D-aspartate (NMDA) receptors and endogenous NO formation and that occludes tetanus-induced long-term potentiation (LTP). The experiments were initially aimed at determining the relationship between the NO-induced synaptic depression and rebound potentiation. The adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) partially inhibited the depression produced by the NO donor diethylamine NONOate (300 microM). It also led to a complete block of both the rebound potentiation and the subsequent tetanus-induced LTP. LTP was preserved in the presence of DPCPX if the stimulation frequency was reduced to 0.033 Hz or if the NO application was omitted. The NO-triggered rebound potentiation was restored if the experiment (DPCPX followed by exogenous NO) was conducted in the presence of an NMDA antagonist. The restored potentiation was completely blocked by the NO synthase inhibitor, L-nitroarginine. It is concluded that the NO-induced depression is partially mediated by increased release of endogenous adenosine acting on A1 receptors. Moreover, tonic A1 receptor activation by adenosine protects LTP and the rebound potentiation from being disabled by untimely NMDA receptor activity. Hence, the NO-induced depression and rebound potentiation are linked in the sense that the depression helps to preserve the capacity of the synapses to undergo potentiation. Finally, the results give the first example of exogenous NO eliciting an enduring potentiation of hippocampal synaptic transmission that is dependent on endogenous NO formation, but not on NMDA receptors.     

Long-term potentiation facilitates behavioral responding to single-pulse stimulation of the perforant path

Three experiments were conducted to determine whether long-term potentiation (LTP) could enhance the stimulus properties of electrical brain stimulation. First, a paradigm was developed in which single-pulse stimulation of the perforant path (PP) could acquire control over operant responses. Evoked potentials were recorded from the dentate gyrus (DG) on every trial in order to measure the postsynaptic consequences of the stimulus and to monitor synaptic efficacy in the PP-DG synapses. The second experiment confirmed the relation between the amount of evoked activity and acquisition rate and also showed that transecting the PP impaired performance. In the third experiment, high-frequency stimulation of the PP produced LTP and accelerated subsequent acquisition of behavioral responding to PP stimulation. These results document a clear link between increases in synaptic efficacy and changes in behavior and thereby demonstrate the ability of LTP to serve as at least one component of the neural bases of learning and memory.     

Synaptic plasticity in the subiculum

The subiculum is the principal target of CA1 pyramidal cells. It functions as a mediator of hippocampal–cortical interaction and has been proposed to play an important role in the encoding and retrieval of long-term memory. The cellular mechanisms of memory formation are thought to include long-term potentiation (LTP) and depression (LTD) of synaptic strength. This review summarizes the contemporary knowledge of LTP and LTD at CA1–subiculum synapses. The observation that the underlying mechanisms of LTP and LTD at CA1–subiculum synapses correlate with the discharge properties of subicular pyramidal cell reveals a novel and intriguing mechanism of cell-specific consolidation of hippocampal output.     

Synaptic plasticity in the subiculum

The subiculum is the principal target of CA1 pyramidal cells. It functions as a mediator of hippocampal–cortical interaction and has been proposed to play an important role in the encoding and retrieval of long-term memory. The cellular mechanisms of memory formation are thought to include long-term potentiation (LTP) and depression (LTD) of synaptic strength. This review summarizes the contemporary knowledge of LTP and LTD at CA1–subiculum synapses. The observation that the underlying mechanisms of LTP and LTD at CA1–subiculum synapses correlate with the discharge properties of subicular pyramidal cell reveals a novel and intriguing mechanism of cell-specific consolidation of hippocampal output.     

Surprising similarity between mechanisms mediating low (1 Hz)-and high (100 Hz)-induced long-lasting synaptic potentiation in CA1 of the intact hippocampus

It is generally assumed that long lasting synaptic potentiation (long-term potentiation, LTP) and depression (long-term depression, LTD) result from distinct patterns of afferent activity, with high and low frequency activity favouring LTP and LTD, respectively. However, a novel form of N-methyl-d-aspartate (NMDA) receptor-dependent synaptic potentiation in the hippocampal CA1 area in vivo induced by low frequency afferent stimulation has recently been demonstrated. Here, we further characterize the mechanisms mediating this low frequency stimulation (LFS)-induced LTP in area CA1 of intact, urethane-anesthetized preparations. Consistent with previous reports, alternating, low frequency (1 Hz) stimulation of CA1 afferents originating in the contralateral CA3 area and the medial septum resulted in gradually developing, long lasting (>2 h) LTP of field excitatory postsynaptic potentials (fEPSPs) recorded in CA1. Local application of the protein synthesis inhibitor anisomycin in CA1 blocked LFS-induced LTP, as did application of H89, an inhibitor of protein kinase A. Given the apparent overlap in molecular mechanisms mediating LFS-LTP and “classic” high-frequency stimulation (HFS)-induced LTP in CA1, we examined the relation between these forms of LTP by means of occlusion experiments. LFS, delivered to synapses saturated by initial HFS, resulted in a gradually developing LTD, rather than the normally seen LTP. Conversely, initial induction of LFS-LTP reduced the amount of subsequent HFS-LTP. Together, these experiments reveal a surprising similarity in the molecular mechanisms (dependence on NMDA receptors, protein kinase A, protein synthesis) mediating LTP induced by highly distinct (1 vs. 100 Hz) induction protocols. Importantly, these findings further challenge the “high-frequency-LTP, low-frequency LTD” dogma by demonstrating that this dichotomy does not account for all types of plasticity phenomena at central synapses.     

Late phase of long-term potentiation induced by co-application of N-methyl-d-aspartic acid and the antagonist of NR2B-containing N-methyl-d-aspartic acid receptors in rat hippocampus

Activation of N-methyl-d-aspartic acid (NMDA) glutamate receptors (NMDARs) is required for long-term potentiation (LTP) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular mechanisms of learning and memory. We demonstrate here that a brief bath co-application of a low concentration of NMDA, an agonist of NMDARs, and the selective antagonist of NR2B-containing NMDARs, (α R, β S)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), to hippocampal slices from young adult rats produced a slowly developing LTP persisting at least for 6 h following a transient depression of synaptic transmission in CA1 synapses. The LTP was likely to occur at postsynaptic site and was initiated by activation of NMDARs, and its development was mediated by cAMP-dependent protein kinase (PKA) activation and protein synthesis. This chemically induced LTP and the tetanus-induced late phase of LTP (L-LTP) were mutually occluding, suggesting a common expression mechanism. Thus, we have demonstrated that a brief bath co-application of NMDA with Ro25-6981 to a slice offers an alternative to electrical stimulation as a stimulation method to induce L-LTP. The chemically induced LTP did not require the low-frequency test stimulation typically used to monitor the strength of synapses during and after drug application. Thus, the LTP may occur at a large fraction of synapses in the slice and not to be confined to a small fraction of the synapses where electrical stimulation can reach and induce LTP. Therefore, this chemically induced LTP may be useful for assessing the biochemical and morphological correlates and the molecular aspects of the expression mechanism for L-LTP that has been proven to correlate to hippocampal long-term memory.     

In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity

Extracellular proteolysis is an important regulatory nexus for coordinating synaptic functional and structural plasticity, but the identity of such proteases is incompletely understood. Matrix metalloproteinases (MMPs) have well-known, mostly deleterious roles in remodeling after injury or stroke, but their role in nonpathological synaptic plasticity and function in intact adult brains has not been extensively investigated. Here we address the role of MMP-9 in hippocampal synaptic plasticity using both gain- and loss-of-function approaches in urethane-anesthetized adult rats. Acute blockade of MMP-9 proteolytic activity with inhibitors or neutralizing antibodies impairs maintenance, but not induction, of long-term potentiation (LTP) at synapses formed between Schaffer-collaterals and area CA1 dendrites. LTP is associated with significant increases in levels of MMP-9 and proteolytic activity within the potentiated neuropil. By introducing a novel application of gelatin-substrate zymography in vivo, we find that LTP is associated with significantly elevated numbers of gelatinolytic puncta in the potentiated neuropil that codistribute with immunolabeling for MMP-9 and for markers of synapses and dendrites. Such increases in proteolytic activity require NMDA receptor activation. Exposing intact area CA1 neurons to recombinant-active MMP-9 induces a slow synaptic potentiation that mutually occludes, and is occluded by, tetanically evoked potentiation. Taken together, our data reveal novel roles for MMP-mediated proteolysis in regulating nonpathological synaptic function and plasticity in mature hippocampus.     

Bi-directional changes in synaptic plasticity induced at corticostriatal synapses in vitro

Long-term changes in the synaptic efficacy of corticostriatal synapses are believed to be important for regulating the excitatory input to the basal ganglia, and hence for motor learning and certain forms of cognition. Previous reports have suggested that long-term depression (LTD) is the predominant form of plasticity at corticostriatal synapses. However, we report here that tetanic stimulation of the white matter can readily induce long-term potentiation (LTP) at corticostriatal synapses in a sagittal slice preparation. Furthermore, we find that corticostriatal LTP is obtained in the absence of pharmacological manipulation, and is dependent on NMDA receptor activation. In contrast, LTD is rarely observed following tetanic stimulation of the white matter, but in fact requires direct stimulation within the striatum. This striatally induced depression is blocked by both D1 and D2 dopamine receptor antagonists and by NMDA receptor blockade. Pairing of striatal stimulation with tetanic stimulation of the white matter does not prevent the induction, but significantly enhances the magnitude of LTP at corticostriatal synapses. We suggest that the corticostriatal depression reported here most likely involves the recruitment of local striatal circuits and dopaminergic inputs, and thus might explain the predominance of LTD previously reported. Our observation that it is indeed possible to induce LTP at corticostriatal synapses under physiological conditions in vitro has implications for the normal function and control of the basal ganglia in motor learning and cognition.     

Coexistence of muscarinic long-term depression with electrically induced long-term potentiation and depression at CA3-CA1 synapses

Our laboratory recently characterized a form of long-term depression (LTD) at CA3-CA1 synapses mediated by M1 muscarinic receptors (mAChRs), termed muscarinic LTD (mLTD). mLTD is both activity and NMDAR dependent, characteristics shared by forms of synaptic plasticity thought to be relevant to learning and memory, including long-term potentiation (LTP) induced by high-frequency stimulation (HFS-LTP) and long-term depression induced by low-frequency stimulation (LFS-LTD). However, it remains unclear whether mLTD can occur sequentially with these electrically induced forms of hippocampal plasticity or whether mLTD might interact with them. The first goal of this study was to examine the interplay of mLTD and HFS-LTP. We report that mLTD expression does not alter subsequent induction of HFS-LTP and, further, at synapses expressing HFS-LTP, mLTD can mediate a novel form of depotentiation. The second goal was to determine whether mLTD would alter LFS-LTD induction and/or expression. Although we show that mLTD is occluded by saturation of LFS-LTD, suggesting mechanistic similarity between these two plasticities, saturation of mLTD does not occlude LFS-LTD. Surprisingly, however, the LFS-LTD that follows cholinergic receptor activation is NMDAR independent, indicating that application of muscarinic agonist induces a change in the induction mechanism required for LFS-LTD. These data demonstrate that mLTD can coexist with electrically induced forms of synaptic plasticity and support the hypothesis that mLTD is one of the mechanisms by which the cholinergic system modulates hippocampal function.     

Impaired synaptic plasticity in mice carrying the Huntington's disease mutation

Cognitive impairment is an early symptom of Huntington's disease (HD). Mice engineered to carry the HD mutation in the endogenous huntingtin gene showed a significant reduction in long-term potentiation (LTP), a measure of synaptic plasticity often thought to be involved in memory. However, LTP could be induced in mutant slices by an 'enhanced' tetanic stimulus, implying that the LTP-producing mechanism is intact in mutant mice, but that their synapses are less able to reach the threshold for LTP induction. Mutant mice showed less post-tetanic potentiation than wild-type animals, and also showed decreased paired pulse facilitation, suggesting that excitatory synapses in HD mutant mice are impaired in their ability to sustain transmission during repetitive stimulation. We show that mutants, while normal in their ability to transmit at low frequencies, released significantly less glutamate during higher frequency synaptic activation. Thus, a reduced ability of Huntington synapses to respond to repetitive synaptic demand of even moderate frequency could result not only in a functional impairment of LTP induction, but could also serve as a substrate for the cognitive symptoms that comprise the early-stage pathology of HD.     

Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum

Various forms of synaptic plasticity underlying motor learning have already been well characterized at cerebellar parallel fibre (PF)–Purkinje cell (PC) synapses. Inhibitory interneurones play an important role in controlling the excitability and synchronization of PCs. We have therefore tested the possibility that excitatory synapses between PFs and stellate cells (SCs) are also able to exhibit long-term changes in synaptic efficacy. In the present study, we show that long-term potentiation (LTP) and long-term depression (LTD) were induced at these synapses by a low frequency stimulation protocol (2 Hz for 60 s) and that pairing this low frequency stimulation protocol with postsynaptic depolarization induced a marked shift of synaptic plasticity in favour of LTP. This LTP was cAMP independent, but required nitric oxide (NO) production from pre- and/or postsynaptic elements, depending on the stimulation or pairing protocol used, respectively. In contrast, LTD was not dependent on NO production but it required activation of postsynaptic group II and possibly of group I metabotropic glutamate receptors. Finally, stimulation of PFs at 8 Hz for 15 s also induced LTP at PF–SC synapses. But in this case, LTP was cAMP dependent, as was also observed at PF–PC synapses for presynaptic LTP induced in the same conditions. Thus, long-term changes in synaptic efficacy can be accomplished by PF–SCs synapses as well as by PF–PC synapses, suggesting that both types of plasticity might co-operate during cerebellar motor learning.     

Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent

Chemically induced long-term potentiation (cLTP) could potentially work by directly stimulating the biochemical machinery that underlies synaptic plasticity, bypassing the need for synaptic activation. Previous reports suggested that agents that raise cAMP concentration might have this capability. We examined the cLTP induced in acute slices by application of Sp-cAMPS or a combination of the adenylyl cyclase activator, forskolin, and the phosphodiesterase inhibitor, rolipram. Under our conditions, cLTP was induced but only if inhibition was reduced. We found that this form of cLTP was blocked by a N-methyl-d-aspartate receptor (NMDAR) antagonist and required the low-frequency test stimulation typically used to monitor the strength of synapses. Interestingly, similar LTP could be induced by lowering the Mg(2+) concentration of the ACSF during forskolin/rolipram or Sp-cAMPS application or even by just lowering Mg(2+) concentration alone. This LTP was also NMDAR dependent and required only a few ( approximately 5) low-frequency stimuli for its induction. The finding that even low-frequency synaptic stimulation was sufficient for LTP induction indicates that a highly sensitized plasticity state was generated. The fact that some stimulation was required means that potentiation is probably restricted to the stimulated axons, limiting the usefulness of this form of cLTP. However, when similar experiments were conducted using slice cultures, potentiation occurred without test stimuli, probably because the CA3-CA1 connections are extensive and because presynaptic spontaneous activity is sufficient to fulfill the activity requirement. As in acute slices, the potentiation was blocked by an NMDAR antagonist. Our general conclusion is that the induction of LTP caused by elevating cAMP requires presynaptic activity and NMDA channel opening. The method of inducing cLTP in slice cultures will be useful when it is desirable to produce NMDAR-dependent LTP in a large fraction of synapses.     

Gene targeting reveals a role for the glutamate receptors mGluR5 and GluR2 in learning and memory

This work suggests that class I mGluRs are involved in long-term potentiation (LTP) at CA1 synapses within the hippocampus. Our data support a pathway linking class I-mGluRs with PKC and src to enhance the open probability of the NMDAR channel. This leads to LTP of the NMDAR, but not the AMPAR. We are currently analyzing double mGluR1 X mGluR5 knockouts with Collingridge for a loss of the LTP induction switch [Nature 368 (1994) 740.]. This induction of LTP of the NMDAR is necessary for "spatial" learning and memory to occur, since mice lacking the mGluR5 are deficient in the Morris water maze and context-dependent fear conditioning. We postulate that AMPARs may provide negative feedback inhibition to the NMDAR. Hence, in null mutants lacking the AMPAR subtype, GluR2, LTP in the CA1 region of hippocampal slices was markedly enhanced (twofold) and non-saturating, whereas neuronal excitability and paired-pulse facilitation were normal. The ninefold increase in Ca(2+) permeability, in response to kainate application, suggests one possible mechanism for enhanced LTP. Enhanced LTP could result from enhanced AMPAR channel conductance or increased recruiting of previously silent synapses. Since the GluR2 null mutants showed reduced exploration and impaired motor coordination, we could make no conclusion about its role in learning and memory. Future work will be directed to inducible deletion of GluR2 only in CA1 after development is complete. These results support the correlation between LTP and learning and memory.     

Input-and layer-dependent synaptic plasticity in the rat perirhinal cortex in vitro.

The perirhinal cortex is crucially important in several forms of memory. Whilst it is important to understand the underlying mechanisms of this role in memory, little is known about the synaptic physiology or plasticity of this region of transitional cortex. In this study, we recorded evoked field potentials in superficial layers (approximately layer I) of the perirhinal cortex in vitro. One stimulating electrode was placed on the temporal side and the other on the entorhinal side of the rhinal sulcus in either the superficial or intermediate layers (approximately layers II/III). Paired stimuli resulted in depression of the second response. Paired-pulse depression was maximal at a 200-ms interpulse interval. Low-frequency stimulation resulted in synaptic depression, which returned to baseline within 60 min. The magnitude of both paired-pulse depression and low-frequency stimulation-induced depression was significantly greater at synapses activated from the temporal intermediate pathway than the other three pathways. Long-term potentiation, stable for at least 60 min, was induced by high-frequency stimulation of intermediate but not superficial pathways. Long-lasting depression (depotentiation) was induced by low-frequency stimulation following the induction of long-term potentiation. The induction of both long-term potentiation and depotentiation was N-methyl-D-aspartate receptor dependent. The group I/II metabotropic glutamate receptor antagonist (S)-alpha-methyl-4-carboxyphenylglycine was without effect on either of these forms of plasticity. Thus, both long- and short-lasting forms of synaptic plasticity exist at synapses in the perirhinal cortex, and these may mediate the changes in neuronal responses associated with visual recognition memory.     

Activation of spinal d1/d5 receptors induces late-phase LTP of C-fiber-evoked field potentials in rat spinal dorsal horn

Long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn may be relevant to pathological pain. Our previous work has shown that the late phase of the spinal LTP is protein synthesis-dependent. Considerable evidence has accumulated that dopamine D1/D5 receptors are important for late-phase LTP in hippocampus. In this study, the role of D1/D5 receptors in LTP of C-fiber-evoked field potentials in spinal dorsal horn was evaluated in urethan-anesthetized Sprague-Dawley rats. We found the following. 1) Spinal application of SKF 38393, a D1/D5 receptor agonist, induced a slowly developed LTP of C-fiber-evoked field potentials, lasting for >10 h, and the effect was blocked by the D1/D5 antagonist SCH 23390, whereas a D2 receptor agonist (quinpirole) induced depression of C-fiber responses, lasting for 2 h. 2) The potentiation produced by D1/D5 receptor agonist occluded the late phase but not the early phase of the spinal LTP produced by tetanic stimulation. 3) SCH 23390 selectively depressed the late-phase LTP, when applied 40 min before tetanic stimulation. 4) The D1/D5 agonist-induced potentiation is blocked by the protein synthesis inhibitor anisomycin. 5) Activation of protein kinase A by spinal application of 8-Br-cAMP also induced spinal LTP, and the action occluded the potentiation induced by the D1/D5 receptor agonist. These results suggest that the spinal D1/D5 receptors participate in the protein synthesis-dependent late-phase LTP of C-fiber-evoked field potentials in spinal dorsal horn through the cAMP signaling pathway.     

AMPA silencing is a prerequisite for developmental long-term potentiation in the hippocampal CA1 region

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) unsilencing is an often proposed expression mechanism both for developmental long-term potentiation (LTP), involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3-CA1 connection na?ve (nonstimulated) synapses are AMPA signaling and AMPA-silent synapses are created from na?ve AMPA-signaling (AMPA-labile) synapses by test-pulse synaptic activation (AMPA silencing). To investigate to what extent LTPs at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the na?ve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the na?ve synaptic strength. Thus this early, or developmental, LTP is nothing more than an unsilencing (dedepression) and stabilization of the AMPA signaling that was lost by the prior AMPA silencing. This dedepression and stabilization of AMPA signaling was mimicked by the presence of the protein kinase A activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a "genuine" potentiation (as opposed to a dedepression) not explained by unsilencing and stabilization of AMPA-labile synapses. This "genuine," or mature, LTP rose from close to nothing of total LTP prior to postnatal day (P)13, to about 70% of total LTP at P16, and to about 90% of total LTP at P30. Developmental LTP, by stabilization of AMPA-labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.     

SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala

At glutamatergic synapses, calcium influx through NMDA receptors (NMDARs) is required for long-term potentiation (LTP); this is a proposed cellular mechanism underlying memory and learning. Here we show that in lateral amygdala pyramidal neurons, SK channels are also activated by calcium influx through synaptically activated NMDARs, resulting in depression of the synaptic potential. Thus, blockade of SK channels by apamin potentiates fast glutamatergic synaptic potentials. This potentiation is blocked by the NMDAR antagonist AP5 (D(-)-2-amino-5-phosphono-valeric acid) or by buffering cytosolic calcium with BAPTA. Blockade of SK channels greatly enhances LTP of cortical inputs to lateral amygdala pyramidal neurons. These results show that NMDARs and SK channels are colocalized at glutamatergic synapses in the lateral amygdala. Calcium influx through NMDARs activates SK channels and shunts the resultant excitatory postsynaptic potential. These results demonstrate a new role for SK channels as postsynaptic regulators of synaptic efficacy.