Synaptosomes and Metamodulation of Receptors.

Synaptosomes are re-sealed pinched off nerve terminals that maintain all the main structural and functional features of the original structures and that are appropriate to study presynaptic events. Because of the discovery of new structural and molecular events that dictate the efficiency of transmitter release and of its receptor-mediated control in the central nervous system, the interest in this tissue preparation is continuously renewing. Most of these events have been already discussed in previous reviews, but few of them were not and deserve some comments since they could suggest new functional and possibly therapeutic considerations. Among them, the "metamodulation" of receptors represents an emerging aspect that dramatically increased the complexity of the presynaptic compartment, adding new insights to the role of presynaptic receptors as modulators of chemical synapses. Deciphering the mechanism of presynaptic metamodulation would permit indirect approaches to control the activity of presynaptic release-regulating receptors that are currently orphans of direct ligands/modulators, paving the road for the proposal of new therapeutic approaches for central neurological diseases.

Presynaptic GABAB receptor inhibition sex dependently enhances fear extinction and attenuates fear renewal.

Anxiety and trauma-related disorders are highly prevalent worldwide, and are associated with altered associative fear learning. Despite the effectiveness of exposure therapy, which aims to reduce associative fear responses, relapse rates remain high. This is due, in part, to the context specificity of exposure therapy, which is a form of extinction. Many studies show that fear relapses when mice are tested outside the extinction context, and this is known as fear renewal. Using Pavlovian fear conditioning and extinction, we can study the mechanisms underlying extinction and renewal. The aim of the current experiment was to identify the role of presynaptic GABAB receptors in these two processes. Previous work from our lab showed that genetic deletion or pharmacological inhibition of GABAB(1a) receptors that provide presynaptic inhibition on glutamatergic terminals reduces context specificity and leads to generalization. We therefore hypothesized that inactivation of these presynaptic GABAB receptors could be used to reduce the context specificity associated with fear extinction training and suppress renewal when mice are tested outside of the extinction context. Using CGP 36216, an antagonist specific for presynaptic GABAB receptors, we blocked presynaptic GABAB receptors using intracerebroventricular injections during various time points of extinction learning in male and female mice. Results showed that blocking these receptors pre- and post-extinction training led to enhanced extinction learning in male mice only. We also found that post-extinction infusions of CGP reduced renewal rates in male mice when they were tested outside of the extinction context. In an attempt to localize the function of presynaptic GABAB receptors within regions of the extinction circuit, we infused CGP locally within the basolateral amygdala or dorsal hippocampus. We failed to reduce renewal when CGP was infused directly within these regions, suggesting that presynaptic inhibition within these regions per se may not be necessary for driving context specificity during extinction learning. Together, these results show an important sex-dependent role of presynaptic GABAB receptors in extinction and renewal processes and identify a novel receptor target that may be used to design pharmacotherapies to enhance the effectiveness of exposure therapy.

The Sex-Specific VC Neurons Are Mechanically Activated Motor Neurons That Facilitate Serotonin-Induced Egg Laying in C. elegans.

Successful execution of behavior requires coordinated activity and communication between multiple cell types. Studies using the relatively simple neural circuits of invertebrates have helped to uncover how conserved molecular and cellular signaling events shape animal behavior. To understand the mechanisms underlying neural circuit activity and behavior, we have been studying a simple circuit that drives egg-laying behavior in the nematode worm Caenorhabditis elegans Here we show that the sex-specific, ventral C (VC) motor neurons are important for vulval muscle contractility and egg laying in response to serotonin. Ca2+ imaging experiments show the VCs are active during times of vulval muscle contraction and vulval opening, and optogenetic stimulation of the VCs promotes vulval muscle Ca2+ activity. Blocking VC neurotransmission inhibits egg laying in response to serotonin and increases the failure rate of egg-laying attempts, indicating that VC signaling facilitates full vulval muscle contraction and opening of the vulva for efficient egg laying. We also find the VCs are mechanically activated in response to vulval opening. Optogenetic stimulation of the vulval muscles is sufficient to drive VC Ca2+ activity and requires muscle contractility, showing the presynaptic VCs and the postsynaptic vulval muscles can mutually excite each other. Together, our results demonstrate that the VC neurons facilitate efficient execution of egg-laying behavior by coordinating postsynaptic muscle contractility in response to serotonin and mechanosensory feedback.SIGNIFICANCE STATEMENT Many animal motor behaviors are modulated by the neurotransmitters, serotonin and ACh. Such motor circuits also respond to mechanosensory feedback, but how neurotransmitters and mechanoreceptors work together to coordinate behavior is not well understood. We address these questions using the egg-laying circuit in Caenorhabditis elegans where we can manipulate presynaptic neuron and postsynaptic muscle activity in behaving animals while recording circuit responses through Ca2+ imaging. We find that the cholinergic VC motoneurons are important for proper vulval muscle contractility and egg laying in response to serotonin. Muscle contraction also activates the VCs, forming a positive feedback loop that promotes full contraction for egg release. In all, mechanosensory feedback provides a parallel form of modulation that shapes circuit responses to neurotransmitters.

BDNF Activates Postsynaptic TrkB Receptors to Induce Endocannabinoid Release and Inhibit Presynaptic Calcium Influx at a Calyx-Type Synapse.

Brain-derived neurotropic factor (BDNF) has been shown to play critical roles in neural development, plasticity, and neurodegenerative diseases. The main function of BDNF in the brain is widely accepted to be synaptic regulation. However, how BDNF modulates synaptic transmission, especially the underlying signaling cascades between presynaptic and postsynaptic neurons, remains controversial. In the present study, we investigated the actions of BDNF at rat calyx-type synapses of either sex by measuring the excitatory postsynaptic current (EPSC) and presynaptic calcium current and capacitance changes. We found that BDNF inhibits the EPSC, presynaptic calcium influx, and exocytosis/endocytosis via activation of the presynaptic cannabinoid Type 1 receptors (CB1Rs). Inhibition of the CB1Rs abolished the BDNF-induced presynaptic inhibition, whereas CB1R agonist mimicked the effect of BDNF. Exploring the underlying signaling cascade, we found that BDNF specifically activates the postsynaptic TrkB receptors, inducing the release of endocannabinoids via the PLCγ/DGL pathway and retrogradely activating presynaptic CB1Rs. We also reported the involvement of AC/PKA in modulating vesicle endocytosis, which may account for the BDNF-induced calcium-dependent and -independent regulation of endocytosis. Thus, our study provides new insights into the BDNF/endocannabinoid-associated modulation of neurotransmission in physiological and pathologic processes.SIGNIFICANCE STATEMENT BDNF plays critical roles in the modulation of synaptic strength. However, how BDNF regulates synaptic transmission and its underlying signaling cascade(s) remains elusive. By measuring EPSC and the presynaptic calcium current and capacitance changes at rat calyces, we found that BDNF inhibits synaptic transmission via BDNF-TrkB-eCB signaling pathway. Activation of postsynaptic TrkB receptors induces endocannabinoid release via the PLCγ/DGL pathway, retrogradely activating the presynaptic CB1Rs, inhibiting the AC/PKA, and suppressing calcium influx. Our findings provide a comprehensive understanding of BDNF/endocannabinoid-associated modulation of neuronal activities.

Postsynaptic GluN2B-containing NMDA receptors contribute to long-term depression induction in medial vestibular nucleus neurons of juvenile rats.

Medial vestibular nucleus (MVN) neurons are involved in the regulation of eye movements to endure the stability of the image during head movement, and play a critical role in plasticity of the vestibulo-ocular reflex (VOR) during the juvenile period. We have previously shown that the long-term depression (LTD) of synaptic transmission was induced by high frequency stimulation (HFS) and blocked by N-methyl-D-aspartate (NMDA) receptor antagonist D-APV at the vestibular afferent synapses of type-B MVN neurons. In the present study, we used whole-cell patch-clamp recordings in vitro to investigate the subunit composition of these NMDA receptors in the induction of LTD in MVN slices from postnatal 13-16 day rats. We found that LTD induced in type-B neurons of the rat MVN with HFS was blocked by Ro 25-6981, a specific antagonist for GluN2B-containing NMDA receptors. Moreover, the other selective GluN2B-containing NMDA receptor antagonist (ifenprodil) also prevented the induction of LTD. However, bath application of the GluN2A-containing NMDA receptor antagonists (Zn2+ and TCN 201) had no influence on the induction of LTD. Similar results were obtained by exogenously applied two GluN2C/GluN2D-preferring NMDA receptor antagonists (PPDA and UBP 141). Furthermore, presynaptic NMDA receptor subunits are not necessary for vestibular LTD. These results suggest that the induction of LTD by HFS in vestibular afferent synapses of type-B MVN neurons requires postsynaptic GluN2B-containing NMDA receptors, but not GluN2A-containing NMDA receptors or GluN2C/GluN2D-containing NMDA receptors.

Presynaptic Release-regulating Metabotropic Glutamate Receptors: An Update.

Metabotropic glutamate (mGlu) receptors represent the largest family of glutamate receptors in mammals and act as fine tuners of the chemical transmission in central nervous system (CNS). In the last decade, results concerning the expression and the subcellular localization of mGlu receptors further clarified their role in physio-pathological conditions. Concomitantly, their pharmacological characterization largely improved thanks to the identification of new compounds (chemical ligands and antibodies recognizing epitopic sequences of the receptor proteins) that allowed to decipher the protein compositions of the naive receptors. mGlu receptors are expressed at the presynaptic site of chemical synapses. Here, they modulate intraterminal enzymatic pathways controlling the migration and the fusion of vesicles to synaptic membranes as well as the phosphorylation of colocalized receptors. Both the control of transmitter exocytosis and the phosphorylation of colocalized receptors elicited by mGlu receptors are relevant events that dictate the plasticity of nerve terminals, and account for the main role of presynaptic mGlu receptors as modulators of neuronal signalling. The role of the presynaptic mGlu receptors in the CNS has been the matter of several studies and this review aims at briefly summarizing the recent observations obtained with isolated nerve endings (we refer to as synaptosomes). We focus on the pharmacological characterization of these receptors and on their receptor-receptor interaction / oligo-dimerization in nerve endings that could be relevant to the development of new therapeutic approaches for the cure of central pathologies.

Circuit-specific control of the medial entorhinal inputs to the dentate gyrus by atypical presynaptic NMDARs activated by astrocytes.

Here, we investigated the properties of presynaptic N-methyl-d-aspartate receptors (pre-NMDARs) at corticohippocampal excitatory connections between perforant path (PP) afferents and dentate granule cells (GCs), a circuit involved in memory encoding and centrally affected in Alzheimer's disease and temporal lobe epilepsy. These receptors were previously reported to increase PP release probability in response to gliotransmitters released from astrocytes. Their activation occurred even under conditions of elevated Mg2+ and lack of action potential firing in the axons, although how this could be accomplished was unclear. We now report that these pre-NMDARs contain the GluN3a subunit conferring them low Mg2+ sensitivity. GluN3a-containing NMDARs at PP-GC synapses are preponderantly presynaptic vs. postsynaptic and persist beyond the developmental period. Moreover, they are expressed selectively at medial-not lateral-PP axons and act to functionally enhance release probability specifically of the medial perforant path (MPP) input to GC dendrites. By controlling release probability, GluN3a-containing pre-NMDARs also control the dynamic range for long-term potentiation (LTP) at MPP-GC synapses, an effect requiring Ca2+ signaling in astrocytes. Consistent with the functional observations, GluN3a subunits in MPP terminals are localized at sites away from the presynaptic release sites, often facing astrocytes, in line with a primary role for astrocytic inputs in their activation. Overall, GluN3A-containing pre-NMDARs emerge as atypical modulators of dendritic computations in the MPP-GC memory circuit.

Elevating Growth Factor Responsiveness and Axon Regeneration by Modulating Presynaptic Inputs.

Despite robust effects on immature neurons, growth factors minimally promote axon regeneration in the adult central nervous system (CNS). Attempting to improve growth-factor responsiveness in mature neurons by dedifferentiation, we overexpressed Lin28 in the retina. Lin28-treated retinas responded to insulin-like growth factor-1 (IGF1) by initiating retinal ganglion cell (RGC) axon regeneration after axotomy. Surprisingly, this effect was cell non-autonomous. Lin28 expression was required only in amacrine cells, inhibitory neurons that innervate RGCs. Ultimately, we found that optic-nerve crush pathologically upregulated activity in amacrine cells, which reduced RGC electrical activity and suppressed growth-factor signaling. Silencing amacrine cells or pharmacologically blocking inhibitory neurotransmission also induced IGF1 competence. Remarkably, RGCs regenerating across these manipulations localized IGF1 receptor to their primary cilia, which maintained their signaling competence and regenerative ability. Thus, our results reveal a circuit-based mechanism that regulates CNS axon regeneration and implicate primary cilia as a regenerative signaling hub.

Long-term depression of presynaptic cannabinoid receptor function at parallel fibre synapses.

KEY POINTS: Inhibition of synaptic responses by activation of presynaptic cannabinoid type-1 (Cb1) receptors is reduced at parallel fibre synapses in the cerebellum following 4 Hz stimulation. Activation of adenylyl cyclase is necessary and sufficient for down-regulation of Cb1 receptors induced by 4 Hz stimulation. 4 Hz stimulation reduces Cb1 receptor function by (i) increasing the rate of endocannabinoid clearance from the synapse and (ii) decreasing expression of Cb1 receptors. ABSTRACT: Cannabinoid type-1 receptors (Cb1R) are expressed in the presynaptic membrane of many synapses, including parallel fibre-Purkinje cell synapses in the cerebellum, where they are involved in short- and long-term plasticity of synaptic responses. We show that Cb1R expression itself is a plastic property of the synapse regulated by physiological activity patterns. We made patch clamp recordings from Purkinje cells in cerebellar slices and assessed Cb1R activity by measuring depolarization-induced suppression of excitation (DSE). We find that DSE is normally stable at parallel fibre synapses but, following 4 Hz stimulation, DSE is persistently reduced and recovers more rapidly. Using a combination of electrophysiology, pharmacology and biochemistry, we show that changes in DSE are a result of the reduced expression of Cb1Rs and increased degradation of endocannabinoids by monoacylglycerol lipase. Long-term changes in presynaptic Cb1R expression may alter other forms of Cb1R-dependent plasticity at parallel fibre synapses, priming or inhibiting the circuit for associative learning.

Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain.

Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.

In vivo measurement of afferent activity with axon-specific calcium imaging.

In vivo calcium imaging from axons provides direct interrogation of afferent neural activity, informing the neural representations that a local circuit receives. Unlike in somata and dendrites, axonal recording of neural activity-both electrically and optically-has been difficult to achieve, thus preventing comprehensive understanding of neuronal circuit function. Here we developed an active transportation strategy to enrich GCaMP6, a genetically encoded calcium indicator, uniformly in axons with sufficient brightness, signal-to-noise ratio, and photostability to allow robust, structure-specific imaging of presynaptic activity in awake mice. Axon-targeted GCaMP6 enables frame-to-frame correlation for motion correction in axons and permits subcellular-resolution recording of axonal activity in previously inaccessible deep-brain areas. We used axon-targeted GCaMP6 to record layer-specific local afferents without contamination from somata or from intermingled dendrites in the cortex. We expect that axon-targeted GCaMP6 will facilitate new applications in investigating afferent signals relayed by genetically defined neuronal populations within and across specific brain regions.

Prostaglandin E2 depresses GABA release onto parvocellular neuroendocrine neurones in the paraventricular nucleus of the hypothalamus via presynaptic receptors.

Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and the ensuing release of anti-inflammatory glucocorticoids are critical for the fine-tuning of the inflammatory response. This immune-induced neuroendocrine response is in large part mediated by prostaglandin E2 (PGE2 ), the central actions of which ultimately translate into the excitation of parvocellular neuroendocrine cells (PNCs) in the hypothalamic paraventricular nucleus. However, the neuronal mechanisms by which PGE2 excites PNCs remain incompletely understood. In the present study, we report that PGE2 potently depresses GABAergic inhibitory synaptic transmission onto PNCs. Using whole-cell patch clamp recordings obtained from PNCs in ex vivo hypothalamic slices from rats, we found that bath application of PGE2 (0.01-100 µmol L-1 ) concentration-dependently decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs) with maximum effects at 10 µmol L-1 . The PGE2 -mediated depression of eIPSCs had a rapid onset and was long-lasting, and also was accompanied by an increase in paired pulse ratio. In addition, PGE2 decreased the frequency but not the amplitude of both spontaneous IPSCs and miniature IPSCs. These results collectively indicate that PGE2 acts at a presynaptic locus to decrease the probability of GABA release. Using pharmacological approaches, we also demonstrated that the EP3 subtype of the PGE2 receptor mediated the actions of PGE2 on GABA synapses. Taken together, our results show that PGE2 , via actions of presynaptic EP3 receptors, potently depresses GABA release onto PNCs, providing a plausible mechanism for the disinhibition of HPA axis output during inflammation.

Synaptic nanomodules underlie the organization and plasticity of spine synapses.

Experience results in long-lasting changes in dendritic spine size, yet how the molecular architecture of the synapse responds to plasticity remains poorly understood. Here a combined approach of multicolor stimulated emission depletion microscopy (STED) and confocal imaging in rat and mouse demonstrates that structural plasticity is linked to the addition of unitary synaptic nanomodules to spines. Spine synapses in vivo and in vitro contain discrete and aligned subdiffraction modules of pre- and postsynaptic proteins whose number scales linearly with spine size. Live-cell time-lapse super-resolution imaging reveals that NMDA receptor-dependent increases in spine size are accompanied both by enhanced mobility of pre- and postsynaptic modules that remain aligned with each other and by a coordinated increase in the number of nanomodules. These findings suggest a simplified model for experience-dependent structural plasticity relying on an unexpectedly modular nanomolecular architecture of synaptic proteins.

Bidirectional and long-lasting control of alcohol-seeking behavior by corticostriatal LTP and LTD.

Addiction is proposed to arise from alterations in synaptic strength via mechanisms of long-term potentiation (LTP) and depression (LTD). However, the causality between these synaptic processes and addictive behaviors is difficult to demonstrate. Here we report that LTP and LTD induction altered operant alcohol self-administration, a motivated drug-seeking behavior. We first induced LTP by pairing presynaptic glutamatergic stimulation with optogenetic postsynaptic depolarization in the dorsomedial striatum, a brain region known to control goal-directed behavior. Blockade of this LTP by NMDA-receptor inhibition unmasked an endocannabinoid-dependent LTD. In vivo application of the LTP-inducing protocol caused a long-lasting increase in alcohol-seeking behavior, while the LTD protocol decreased this behavior. We further identified that optogenetic LTP and LTD induction at cortical inputs onto striatal dopamine D1 receptor-expressing neurons controlled these behavioral changes. Our results demonstrate a causal link between synaptic plasticity and alcohol-seeking behavior and suggest that modulation of this plasticity may inspire a therapeutic strategy for addiction.

Towards resolving the presynaptic NMDA receptor debate.

In the classical view, postsynaptic NMDA receptors (NMDARs) trigger Hebbian plasticity via Ca2+ influx. However, unconventional presynaptic NMDARs (preNMDARs) which regulate both long-term and short-term plasticity at several synapse types have also been found. A lack of sufficiently specific experimental manipulations and a poor understanding of how preNMDARs signal have contributed to long-standing controversy surrounding these receptors. Although several prior studies linked preNMDARs to neocortical timing-dependent long-term depression (tLTD), a recent study argues that the NMDARs are actually postsynaptic and signal metabotropically, that is, without Ca2+. Other recent work indicates that, whereas ionotropic preNMDARs signaling controls evoked release, spontaneous release is regulated by metabotropic NMDAR signaling. We argue that elucidating unconventional NMDAR signaling modes-both presynaptically and metabotropically-is key to resolving the preNMDAR debate.

Impact of presynaptic sympathetic imbalance in long-QT syndrome by positron emission tomography.

OBJECTIVE: We investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11C-meta-hydroxyephedrine ([11C]mHED-PET). METHODS: [11C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [11C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity. RESULTS: Global and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean ±SD; 0.08±0.14 vs 0.00%±0.09% min-1; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values. CONCLUSION: The increased regional WO rate of [11C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance ß-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS. TRIAL REGISTRATION NUMBER: 2006-002767-41;Results.

Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors.

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg2+-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αß deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg2+-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT.

Retinal and Nonretinal Contributions to Extraclassical Surround Suppression in the Lateral Geniculate Nucleus.

Extraclassical surround suppression is a prominent receptive field property of neurons in the lateral geniculate nucleus (LGN) of the dorsal thalamus, influencing stimulus size tuning, response gain control, and temporal features of visual responses. Despite evidence for the involvement of both retinal and nonretinal circuits in the generation of extraclassical suppression, we lack an understanding of the relative roles played by these pathways and how they interact during visual stimulation. To determine the contribution of retinal and nonretinal mechanisms to extraclassical suppression in the feline, we made simultaneous single-unit recordings from synaptically connected retinal ganglion cells and LGN neurons and measured the influence of stimulus size on the spiking activity of presynaptic and postsynaptic neurons. Results show that extraclassical suppression is significantly stronger for LGN neurons than for their retinal inputs, indicating a role for extraretinal mechanisms. Further analysis revealed that the enhanced suppression can be accounted for by mechanisms that suppress the effectiveness of retinal inputs in evoking LGN spikes. Finally, an examination of the time course for the onset of extraclassical suppression in the LGN and the size-dependent modulation of retinal spike efficacy suggests the early phase of augmented suppression involves local thalamic circuits. Together, these results demonstrate that the LGN is much more than a simple relay for retinal signals to cortex; it also filters retinal spikes dynamically on the basis of stimulus statistics to adjust the gain of visual signals delivered to cortex. SIGNIFICANCE STATEMENT: The lateral geniculate nucleus (LGN) is the gateway through which retinal information reaches the cerebral cortex. Within the LGN, neuronal responses are often suppressed by stimuli that extend beyond the classical receptive field. This form of suppression, called extraclassical suppression, serves to adjust the size tuning, response gain, and temporal response properties of neurons. Given the important influence of extraclassical suppression on visual signals delivered to cortex, we performed experiments to determine the circuit mechanisms that contribute to extraclassical suppression in the LGN. Results show that suppression is augmented beyond that provided by direct retinal inputs and delayed, consistent with polysynaptic inhibition. Importantly, these mechanisms influence the effectiveness of incoming retinal signals, thereby filtering the signals ultimately conveyed to cortex.

Effects of Etomidate on GABAergic and Glutamatergic Transmission in Rat Thalamocortical Slices.

Although accumulative evidence indicates that the thalamocortical system is an important target for general anesthetics, the underlying mechanisms of anesthetic action on thalamocortical neurotransmission are not fully understood. The aim of the study is to explore the action of etomidate on glutamatergic and GABAergic transmission in rat thalamocortical slices by using whole cell patch-clamp recording. We found that etomidate mainly prolonged the decay time of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs), without changing the frequency. Furthermore, etomidate not only prolonged the decay time of miniature inhibitory postsynaptic currents (mIPSCs) but also increased the amplitude. On the other hand, etomidate significantly decreased the frequency of spontaneous glutamatergic excitatory postsynaptic currents (sEPSCs), without altering the amplitude or decay time in the absence of bicuculline. When GABAA receptors were blocked using bicuculline, the effects of etomidate on sEPSCs were mostly eliminated. These results suggest that etomidate enhances GABAergic transmission mainly through postsynaptic mechanism in thalamocortical neuronal network. Etomidate attenuates glutamatergic transmission predominantly through presynaptic action and requires presynaptic GABAA receptors involvement.

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia.

Schizophrenia is a serious psychiatric illness which is experienced by about 1 % of individuals worldwide and has a debilitating impact on perception, cognition, and social function. Over the years, several models/hypotheses have been developed which link schizophrenia to dysregulations of the dopamine, glutamate, and serotonin receptor pathways. An important segment of these pathways that have been extensively studied for the pathophysiology of schizophrenia is the presynaptic neurotransmitter release mechanism. This set of molecular events is an evolutionarily well-conserved process that involves vesicle recruitment, docking, membrane fusion, and recycling, leading to efficient neurotransmitter delivery at the synapse. Accumulated evidence indicate dysregulation of this mechanism impacting postsynaptic signal transduction via different neurotransmitters in key brain regions implicated in schizophrenia. In recent years, after ground-breaking work that elucidated the operations of this mechanism, research efforts have focused on the alterations in the messenger RNA (mRNA) and protein expression of presynaptic neurotransmitter release molecules in schizophrenia and other neuropsychiatric conditions. In this review article, we present recent evidence from schizophrenia human postmortem studies that key proteins involved in the presynaptic release mechanism are dysregulated in the disorder. We also discuss the potential impact of dysfunctional presynaptic neurotransmitter release on the various neurotransmitter systems implicated in schizophrenia.