PACAP-38 enhances excitatory synaptic transmission in the rat hippocampal CA1 region

Specific receptors for pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide with neuroregulatory and neurotrophic functions, have been identified recently in different brain regions, including the hippocampus. In this study, we examined the effects of PACAP-38 on the excitatory postsynaptic field potentials (fEPSPs) evoked at the Schaffer collateral-CA1 synapses. Brief bath application of PACAP-38 (0.05 nM) induced a long-lasting facilitation of the basal transmission. Enhancement of this response was occluded in part by previous high-frequency-induced long-term potentiation (LTP). PACAP-38 did not significantly alter the paired-pulse facilitation (PPF). PACAP-38 has been shown to have a presynaptic effect on the septohippocampal cholinergic terminals, which results in an increase in basal acetylcholine (ACh) release. To assess whether the PACAP-38 enhancement of CA1 synapses was related to the activation of the cholinergic system we examined the effect of this peptide in the presence of atropine, a muscarinic receptor antagonist. The enhancement of the fEPSPs by PACAP-38 was blocked by bath application of atropine. These results show that PACAP-38 induces facilitation of hippocampal synaptic transmission through activation of the cholinergic system via the muscarinic receptors.     

Insights into a molecular switch that gates sensory neuron synapses during habituation in Aplysia

This review focuses on synaptic depression at sensory neuron-to-motor neuron synapses in the defensive withdrawal circuit of Aplysia as a model system for analysis of molecular mechanisms of sensory gating and habituation. We address the following topics:1. Of various possible mechanisms that might underlie depression at these sensory neuron-to-motor neuron synapses in Aplysia, historically the most widely-accepted explanation has been depletion of the readily releasable pool of vesicles. Depletion is also believed to account for synaptic depression at long interstimulus intervals in a variety of other systems.2. Multiple lines of evidence now indicate that vesicle depletion is not an important contributing mechanism to synaptic depression at Aplysia sensory neuron-to-motor neuron synapses. More generally, it appears that vesicle depletion does not contribute substantially to depression that occurs with those stimulus patterns that are typically used in studying behavioral habituation.3. Recent evidence suggests that at these sensory neuron-to-motor neuron synapses in Aplysia, synaptic depression is mediated by an activity-dependent, but release-independent, switching of individual release sites to a silent state. This switching off of release sites is initiated by Ca²⁺ influx during individual action potentials. We discuss signaling proteins that may be regulated by Ca²⁺ during the silencing of release sites that underlies synaptic depression.4. Bursts of 2–4 action potentials in presynaptic sensory neurons in Aplysia prevent the switching off of release sites via a mechanism called “burst-dependent protection” from synaptic depression.5. This molecular switch may explain the sensory gating that allows animals to discriminate which stimuli are innocuous and appropriate to ignore and which stimuli are more important and should continue to elicit responses.     

Role of Aplysia cell adhesion molecules during 5-HT-induced long-term functional and structural changes

We previously reported that five repeated pulses of 5-HT lead to down-regulation of the TM-apCAM isoform at the surface of Aplysia sensory neurons (SNs). We here examined whether apCAM down-regulation is required for 5-HT-induced long-term facilitation. We also analyzed the role of the cytoplasmic and extracellular domains by overexpressing various apCAM mutants by DNA microinjection. When TM-apCAM was up-regulated in SNs by DNA microinjection, five pulses of 5-HT failed to produce either synaptic facilitation or an enhancement of synaptic growth, suggesting that down-regulation of apCAM is required for 5-HT-induced EPSP enhancement and new varicosity formation. However, disrupting the extracellular domain function of overexpressed apCAM with a specific antibody restored 5-HT-induced excitatory postsynaptic potential increase but not synaptic growth. The overexpression of the MAP Kinase mutant of TM-apCAM, which is not internalized by 5-HT, inhibited new varicosity formation, but did not inhibit excitatory postsynaptic potential increase. Deletion mutants containing only the cytoplasmic portion of apCAM blocked 5-HT-induced synaptic growth but not excitatory postsynaptic potential increase. Thus, our data suggest that TM-apCAM may act as a suppressor of both synaptic-strength enhancement in pre-existing synapses and of new synaptic varicosity formation in the nonsynaptic region, via different mechanisms.     

Coincident induction of long-term facilitation at sensory-motor synapses in Aplysia: presynaptic and postsynaptic factors

Induction of long-term synaptic changes at one synapse can facilitate the induction of long-term plasticity at another synapse. Here we show that if Aplysia sensory neuron (SN) somata and their remote motor neuron (MN) synapses are simultaneously exposed to serotonin (5HT) pulses, which at either site alone are insufficient to induce long-term facilitation (LTF), processes activated at these sites interact to induce LTF. Coincident induction of LTF requires: (1) that the synaptic pulse occurs within a brief temporal window of the somatic pulse and (2) that local protein synthesis occurs immediately at the synapse, followed by delayed protein synthesis at the soma. LTF at the SN-MN synapses can also be induced with cell-wide application of repeated pulses of 5HT. However, these two forms of LTF differ mechanistically: (1) coincident LTF requires protein synthesis in the postsynaptic motor neuron, whereas repeated 5HT LTF does not, and (2) repeated 5HT LTF is accompanied by intermediate-term (3 h) facilitation, whereas coincident LTF is not. Thus LTF expressed in the same temporal domain can result from different underlying mechanisms.     

Galpha(i2) inhibition of adenylate cyclase regulates presynaptic activity and unmasks cGMP-dependent long-term depression at Schaffer collateral-CA1 hippocampal synapses

Cyclic AMP signaling plays a central role in regulating activity at a number of synapses in the brain. We showed previously that pairing activation of receptors that inhibit adenylate cyclase (AC) and reduce the concentration of cyclic AMP, with elevation of the concentration of cyclic GMP is sufficient to elicit a presynaptically expressed form of LTD at Schaffer collateral-CA1 synapses in the hippocampus. To directly test the role of AC inhibition and G-protein signaling in LTD at these synapses, we utilized transgenic mice that express a mutant, constitutively active inhibitory G protein, Galpha(i2), in principal neurons of the forebrain. Transgene expression of Galpha(i2) markedly enhanced LTD and impaired late-phase LTP at Schaffer collateral synapses, with no associated differences in input/output relations, paired-pulse facilitation, or NMDA receptor-gated conductances. When paired with application of a type V phosphodiesterase inhibitor to elevate the concentration of intracellular cyclic GMP, constitutively active Galpha(i2) expression converted the transient depression normally caused by this treatment to an LTD that persisted after the drug was washed out. Moreover, this effect could be mimicked in control slices by pairing type V phosphodiesterase inhibitor application with application of a PKA inhibitor. Electrophysiological recordings of spontaneous excitatory postsynaptic currents and two-photon visualization of vesicular release using FM1-43 revealed that constitutively active Galpha(i2) tonically reduced basal release probability from the rapidly recycling vesicle pool of Schaffer collateral terminals. Our findings support the hypothesis that inhibitory G-protein signaling acts presynaptically to regulate release, and, when paired with elevations in the concentration of cyclic GMP, converts a transient cyclic GMP-induced depression into a long-lasting decrease in release.     

Bidirectional plasticity in striatonigral synapses: a switch to balance direct and indirect basal ganglia pathways

There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral (direct pathway) synapses are not known. Here, we used electrophysiological techniques to describe dopamine D(1)-receptor-mediated facilitation in striatonigral synapses in the context of its interaction with glutamatergic inputs, probably coming from the subthalamic nucleus (STN) (indirect pathway) and describe a striatonigral cannabinoid-dependent long-term synaptic depression (LTD). It is shown that striatonigral afferents exhibit D(1)-receptor-mediated facilitation of synaptic transmission when NMDA receptors are inactive, a phenomenon that changes to cannabinoid-dependent LTD when NMDA receptors are active. This interaction makes SNr neurons become coincidence-detector switching ports: When inactive, NMDA receptors lead to a dopamine-dependent enhancement of direct pathway output, theoretically facilitating movement. When active, NMDA receptors result in LTD of the same synapses, thus decreasing movement. We propose that SNr neurons, working as logical gates, tune the motor system to establish a balance between both BG pathways, enabling the system to choose appropriate synergies for movement learning and postural support.     

Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis

Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that might form a bridge between short- and long-term plasticity. Consistent with that idea, although short-term term behavioral sensitization in Aplysia involves presynaptic mechanisms, intermediate-term sensitization involves both pre- and postsynaptic mechanisms. However, it has not been known whether that is also true of facilitation in vitro, where a more detailed analysis of the mechanisms involved in the different stages and their interrelations is feasible. To address those questions, we have examined pre- and postsynaptic mechanisms of short- and intermediate-term facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. Whereas short-term facilitation by 1-min 5-HT involves presynaptic PKA and CamKII, intermediate-term facilitation by 10-min 5-HT involves presynaptic PKC and postsynaptic Ca(2+) and CamKII, as well as both pre- and postsynaptic protein synthesis. These results support the idea that the intermediate-term stage is the first to involve both pre- and postsynaptic molecular mechanisms, which could in turn serve as some of the initial steps in a cascade leading to synaptic growth during long-term plasticity.     

Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly correlated with behavioral changes induced by nicotine. Here, we study the effect of chronic oral administration of nicotine on the long-term synaptic potentiation in the amygdala, a key structure for emotional memory. We find that oral administration of nicotine for 7 d produces a significant enhancement of LTP in the amygdala. This facilitation is pathway specific: Nicotine selectively facilitates LTP in the cortical-lateral amygdala pathway, but not the thalamic-lateral and the lateral-basolateral synaptic pathway. The synaptic facilitation induced by a 7-d exposure to nicotine is long-lasting, it persists for 72 h after cessation of nicotine but decays 8 d after its cessation. In contrast, a shorter exposure of nicotine (24 h) induces only a short-lasting facilitation of synaptic plasticity that dissipates 24 and 72 h after cessation of nicotine. The facilitation of LTP in the amygdala after exposure to nicotine is mediated by removal of GABAergic inhibition, is dependent on the activation NMDA receptors, and can be prevented by blocking either α7 or β2 nACh receptors. Our results indicate that chronic exposure to nicotine can promote the induction of long-lasting modifications of synapses in a specific pathway in the amygdala.These changes in synaptic plasticity may contribute to the complex neural adaptations and behaviors caused by nicotine.     

Silent synapses in neural plasticity: current evidence

Silent synapses, defined as structural specializations for neurotransmission that do not produce a physiological response in the receiving cell, may occur frequently in neural circuits. Their recruitment to physiological effectiveness may be an important component of circuit modification. In several nervous systems, evidence from electrophysiological and optophysiological measurements has established a strong case for the existence of silent synapses and for their emergence as active synapses with appropriate stimulation. During normal development and aging, synapses of individual neurons change in number, and many of these may be functionally silent at certain stages of their developmental trajectory. Changes in their status may contribute to shaping the properties of neural pathways during development, often in response to neural activity. In general, it is often difficult to distinguish physiological emergence of pre-established silent synapses from developmental maturation or de novo formation of new synapses. Several possible mechanisms for silent synapses and their recruitment are reviewed. These include incompletely assembled synapses that lack structural components, insufficient availability of key presynaptic proteins, and nonfunctional postsynaptic receptors, or presence of receptors that do not mediate a postsynaptic response except under specific conditions (conditionally silent synapses). The available silent synapses can often be rapidly activated, and conversely, active synapses appear to be rapidly silenced in many instances. These properties enable silent synapses to participate in short-term facilitation and depression. In addition, they may contribute to long-term facilitation and potentiation, especially during development.     

The roles of MAPK cascades in synaptic plasticity and memory in Aplysia: facilitatory effects and inhibitory constraints

Synaptic plasticity is thought to contribute to memory formation. Serotonin-induced facilitation of sensory-motor (SN-MN) synapses in Aplysia is an extensively studied cellular analog of memory for sensitization. Serotonin, a modulatory neurotransmitter, is released in the CNS during sensitization training, and induces three temporally and mechanistically distinct phases of SN-MN synaptic facilitation. The role of protein kinase A and protein kinase C in SN-MN synaptic facilitation is well documented. Recently, it has become clear that mitogen-activated protein kinase (MAPK) cascades also play a critical role in SN-MN plasticity. Here, we summarize the roles of MAPK cascades in synaptic plasticity and memory for sensitization in Aplysia.     

Differential Induction of Long-Term Synaptic Facilitation by Spaced and Massed Applications of Serotonin at Sensory Neuron Synapses of Aplysia californica

Serotonin (5HT)-induced facilitation of synaptic transmission from tail sensory neurons (SNs) to motor neurons (MNs) in the marine mollusc Aplysia provides a cellular model of short- and long-term memory for behavioral sensitization of the tail withdrawal reflex. Synaptic facilitation at these synapses occurs in three temporal phases: short-term (STF, lasting minutes), intermediate-term (ITF, lasting more than an hour), and long-term (LTF, lasting >24 hr). STF, ITF, and LTF differ in their induction requirements: A single brief exposure of 5HT induces STF, whereas five applications are required for ITF and LTF. Moreover, STF and LTF can be induced independently.     

Desensitization of postsynaptic glutamate receptors contributes to high-frequency homosynaptic depression of aplysia sensorimotor connections

Withdrawal reflexes of Aplysia are mediated in part by a monosynaptic circuit of sensory (SN) and motor (MN) neurons. A brief high-frequency burst of spikes in the SN produces excitatory postsynaptic potentials (EPSPs) that rapidly decrease in amplitude during the burst of activity. It is generally believed that this and other (i.e., low-frequency) forms of homosynaptic depression are entirely caused by presynaptic mechanisms (e.g., depletion of releasable transmitter). The present study examines the contribution that desensitization of postsynaptic glutamate receptors makes to homosynaptic depression. Bath application of cyclothiazide, an agent that reduces desensitization of non-NMDA glutamate receptors, reduced high-, but not low-frequency synaptic depression. Thus, a postsynaptic mechanism, desensitization of glutamate receptors, can also contribute to homosynaptic depression of sensorimotor synapses.     

Visual attention to emotion in depression: facilitation and withdrawal processes

Attentional biases for sadness are integral to cognitive theories of depression, but do not emerge under all conditions. Some researchers have argued that depression is associated with delayed withdrawal from, but not facilitated initial allocation of attention toward, sadness. We compared two types of withdrawal processes in clinically depressed and non-depressed individuals: (1) withdrawal requiring overt eye movements during visual search; and (2) covert disengagement of attention in a modified cueing paradigm. We also examined initial allocation of attention towards emotion on the visual search task, allowing comparison of withdrawal and facilitation processes. As predicted, we found no evidence of facilitated attention towards sadness in depressed individuals. However, we also found no evidence of depression-linked differences in withdrawal of attention from sadness on either task, offering no support for the theory that depression is associated with withdrawal rather than initial facilitation of attention.     

Visual attention to emotion in depression: Facilitation and withdrawal processes

Attentional biases for sadness are integral to cognitive theories of depression, but do not emerge under all conditions. Some researchers have argued that depression is associated with delayed withdrawal from, but not facilitated initial allocation of attention toward, sadness. We compared two types of withdrawal processes in clinically depressed and non-depressed individuals: (1) withdrawal requiring overt eye movements during visual search; and (2) covert disengagement of attention in a modified cueing paradigm. We also examined initial allocation of attention towards emotion on the visual search task, allowing comparison of withdrawal and facilitation processes. As predicted, we found no evidence of facilitated attention towards sadness in depressed individuals. However, we also found no evidence of depression-linked differences in withdrawal of attention from sadness on either task, offering no support for the theory that depression is associated with withdrawal rather than initial facilitation of attention.     

Differential effects of PACAP-38 on synaptic responses in rat hippocampal CA1 region

Pituitary adenylate cyclase-activating polypeptide (PACAP-38) is a member of the vasointestinal polypeptide (VIP)/secretin/glucagon family of neuropeptides for which neuroregulatory functions have been postulated. PACAP-38 receptors are expressed in different brain regions, including hippocampus. In this study, we examined the dose-dependent effects of PACAP-38 on the excitatory postsynaptic field potential (fEPSP) evoked at the Schaffer collateral-CA1 synapse in rat hippocampal slices. Bath application of low dose (0.05 nM) of PACAP-38 induced long-lasting facilitation of the fEPSP. This enhancement was blocked by the cholinergic receptor antagonist atropine and partially by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (APV) and therefore, shares a common mechanism with LTP. In contrast, a high dose (1 μM) of PACAP-38 induced a persistent depression of the fEPSP that was not blocked by antagonists of cholinergic receptors (i.e., atropine and mecamylamine), adenosine receptors (i.e., DCPCX), or glutamatergic NMDA receptors (APV). Intermediate doses (0.1–0.5 μM) of PACAP-38 produced an initial decrease of the fEPSP followed by an enhancement. This decrease was not blocked by atropine whereas the facilitation was. These results show that PACAP-38 modulates CA1 synaptic transmission in a dose-dependent manner and that the peptide interacts with cholinergic and glutamatergic systems.     

Central synaptic mechanisms underlie short-term olfactory habituation in Drosophila larvae

Naive Drosophila larvae show vigorous chemotaxis toward many odorants including ethyl acetate (EA). Chemotaxis toward EA is substantially reduced after a 5-min pre-exposure to the odorant and recovers with a half-time of ～20 min. An analogous behavioral decrement can be induced without odorant-receptor activation through channelrhodopsin-based, direct photoexcitation of odorant sensory neurons (OSNs). The neural mechanism of short-term habituation (STH) requires the (1) rutabaga adenylate cyclase; (2) transmitter release from predominantly GABAergic local interneurons (LNs); (3) GABA-A receptor function in projection neurons (PNs) that receive excitatory inputs from OSNs; and (4) NMDA-receptor function in PNs. These features of STH cannot be explained by simple sensory adaptation and, instead, point to plasticity of olfactory synapses in the antennal lobe as the underlying mechanism. Our observations suggest a model in which NMDAR-dependent depression of the OSN-PN synapse and/or NMDAR-dependent facilitation of inhibitory transmission from LNs to PNs contributes substantially to short-term habituation.     

Automatic and volitional semantic processing in aphasia.

The present study investigated the status of semantic information in aphasia by comparing the performances of aphasic and nonaphasic subjects on two tasks: an automatic semantic facilitation task and a volitional task of relatedness judgment. Both the aphasic and nonaphasic groups evidenced a semantic facilitation effect, in an on-line task of semantic processing. However, those aphasics with severe comprehension and naming disturbances (termed low comprehension aphasics) demonstrated considerable difficulty in judging the relatedness between a pictured object and members of that object's semantic field, the severity of the impairment being greater for those pictures that the low comprehension aphasics were unable to name. The pattern of results can best be explained by supposing the structural integrity of the store of semantic information in aphasia, and in particular in low comprehension aphasia: information that is retrieved and manipulated in judgment-mediated tasks with considerable difficulty.