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Variability in serotonin (5-HT) function is associated with individual differences in normal mood and temperament, as well as psychiatric illnesses, all of which are influenced by amygdala function. This study evaluated the acute effects of 5-HT reuptake blockade on amygdala function using pharmacological functional MRI. Eight healthy men completed a double-blind balanced crossover study with the selective 5-HT reuptake inhibitor, citalopram (20 mg infused over 30 min), and normal saline. Amygdala reactivity in response to novel facial expressions was assessed on three successive scans, once before drug/placebo infusion, once early in the infusion, and once at the end of infusion. Acute citalopram administration resulted in concentration-dependent increases in human amygdala reactivity to salient stimuli. The current pattern of 5-HT-mediated amygdala reactivity may represent an important pathway through which SSRIs achieve an antidepressant effect. Intriguingly, our data may also reveal a mechanism contributing to clinical observations of extreme agitation, restlessness, and suicidal ideation in some individuals during acute SSRI treatment. Developing a comprehensive model of how 5-HT modulates human amygdala reactivity supporting behavioral and physiological arousal will be instrumental for our understanding of basic neurobehavioral processes, their dysfunction in psychiatric illnesses, and their contribution to mechanism of treatment response.

Based on animal studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effects. Here, we investigated directly the effects of increased and decreased availability of extracellular dopamine on pain perception in healthy volunteers. In Study 1, participants ingested, in separate sessions, a placebo and a low dose of the centrally acting D2-receptor antagonist sulpiride, intended to increase synaptic dopamine via predominant pre-synaptic blockade. No effects were seen on thermal pain thresholds, tolerance, or temporal summation. Study 2 used the acute phenylalanine and tyrosine depletion (APTD) method to transiently decrease dopamine availability. In one session participants ingested a mixture that depletes the dopamine amino acid precursors, phenylalanine and tyrosine. In the other session they ingested a nutritionally balanced control mixture. APTD led to a small mood-lowering response following aversive thermal stimulation, but had no effects on the perception of cold, warm, or pain stimuli. In both studies the experimental manipulation of dopaminergic neurotransmission was successful as indicated by manipulation checks. The results contradict proposals that dopamine has direct anti-nociceptive effects in acute experimental pain. Based on dopamine's well-known role in reward processing, we hypothesize that also in the context of pain, dopamine acts on stimulus salience and might play a role in the initiation of avoidance behavior rather than having direct antinociceptive effects in acute experimental pain.

The capsaicin receptor transient receptor potential cation channel vanilloid 1 (TRPV1) is activated by various noxious stimuli, and the stimuli are converted into electrical signals in primary sensory neurons. It is believed that cation influx through TRPV1 causes depolarization, leading to the activation of voltage-gated sodium channels, followed by the generation of action potential. Here we report that the capsaicin-evoked action potential could be induced by two components: a cation influx-mediated depolarization caused by TRPV1 activation and a subsequent anion efflux-mediated depolarization via activation of anoctamin 1 (ANO1), a calcium-activated chloride channel, resulting from the entry of calcium through TRPV1. The interaction between TRPV1 and ANO1 is based on their physical binding. Capsaicin activated the chloride currents in an extracellular calcium-dependent manner in HEK293T cells expressing TRPV1 and ANO1. Similarly, in mouse dorsal root ganglion neurons, capsaicin-activated inward currents were inhibited significantly by a specific ANO1 antagonist, T16Ainh-A01 (A01), in the presence of a high concentration of EGTA but not in the presence of BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid]. The generation of a capsaicin-evoked action potential also was inhibited by A01. Furthermore, pain-related behaviors in mice treated with capsaicin, but not with αβ-methylene ATP, were reduced significantly by the concomitant administration of A01. These results indicate that TRPV1–ANO1 interaction is a significant pain-enhancing mechanism in the peripheral nervous system. Significance The capsaicin receptor transient receptor potential cation channel vanilloid 1 (TRPV1) and anoctamin 1 (ANO1) work as receptors activated by noxious stimuli in sensory nerve endings. It is believed that activation of the two channels causes cation influx and anion efflux, respectively, both of which lead to depolarization. We show that ANO1 is activated by calcium ions entering neurons through TRPV1 activation based on their physical binding on the cell membrane. Indeed, both capsaicin-activated inward currents in sensory neurons and capsaicin-induced pain-related behaviors in mice were inhibited significantly by ANO1 blockade. To our knowledge, this is the first evidence for a mechanism by which interaction between TRPV1 and ANO1 functions as a pain-enhancing mechanism.

Glutamate-receptor-like molecule delta2 (GluD2) is selectively expressed on the postsynaptic membranes at parallel fiber to Purkinje cell (PF-PC) synapses in the cerebellum. GluD2 plays critical roles not only in postsynaptic long-term depression but also in the induction of presynaptic differentiation through trans-synaptic interaction with neurexin. However, how GluD2 influences the presynaptic function remains unknown. Here, effects of the deletion of postsynaptic GluD2 on the presynaptic properties were studied focusing on the paired pulse ratio (PPR) of two consecutive EPSC amplitudes, which was larger in GluD2 knockout mice. The PPR difference remained even if saturation of glutamate binding to postsynaptic receptors was suppressed, confirming the presynaptic difference between the genotypes. We then explored the possibility that presynaptic voltage-gated Ca(2+) channels (VGCCs) are affected in GluD2 knockout mice. Application of selective blockers for specific VGCCs indicated that R-type but not P/Q- or N-type VGCC, was affected in the mutant mice. Furthermore, presynaptic long-term potentiation (LTP) at PF-PC synapses, which requires R-type VGCC, was impaired in GluD2 knockout mice. These results suggest that GluD2 deletion impairs presynaptic R-type VGCC, resulting in decreased release of synaptic vesicles, and also in the impairment of presynaptic LTP at PF-PC synapses.

Background Systemic inflammation has been linked to synapse loss and cognitive decline in human patients and animal models. A role for microglial release of pro-inflammatory cytokines has been proposed based on in vivo and primary culture studies. However, mechanisms are hard to study in vivo as specific microglial ablation is challenging and the extracellular fluid cannot be sampled without invasive methods. Primary cultures have different limitations as the intricate multicellular architecture in the brain is not fully reproduced. It is essential to confirm proposed brain-specific mechanisms of inflammatory synapse loss directly in brain tissue. Organotypic hippocampal slice cultures (OHSCs) retain much of the in vivo neuronal architecture, synaptic connections and diversity of cell types whilst providing convenient access to manipulate and sample the culture medium and observe cellular reactions. Methods OHSCs were generated from P6-P9 C57BL/6 mice. Inflammation was induced via addition of lipopolysaccharide (LPS), and cultures were analysed for changes in synaptic proteins, gene expression and protein secretion. Microglia were selectively depleted using clodronate, and the effect of IL1β was assessed using a specific neutralising monoclonal antibody. Results LPS treatment induced loss of the presynaptic protein synaptophysin without altering PSD95 or Aβ protein levels. Depletion of microglia prior to LPS application prevented the loss of synaptophysin, whilst microglia depletion after the inflammatory insult was partially effective, although less so than pre-emptive treatment, indicating a time-critical window in which microglia can induce synaptic damage. IL1β protein and mRNA were increased after LPS addition, with these effects also prevented by microglia depletion. Direct application of IL1β to OHSCs resulted in synaptophysin loss whilst pre-treatment with IL1β neutralising antibody prior to LPS addition prevented a significant loss of synaptophysin but may also impact basal synaptic levels. Conclusions The loss of synaptophysin in this system confirms LPS can act directly within brain tissue to disrupt synapses, and we show that microglia are the relevant cellular target when all major CNS cell types are present. By overcoming limitations of primary culture and in vivo work, our study strengthens the evidence for a key role of microglia-derived IL1β in synaptic dysfunction after inflammatory insult.

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxietyand obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL– and not BLA– and vHipp–NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL–NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its dissociative-like properties and abuse potential. While (2R,6R)-HNK is thought to exert its antidepressant-like effects by potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission, it is unknown how it exerts this effect. The acute synaptic effects of (2R,6R)-HNK were examined by recording field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) in rat hippocampal slices. (2R,6R)-HNK bath application caused a rapid and persistent potentiation of AMPAR-mediated Schaffer collateral (SC)-CA1 fEPSPs in slices derived from male and female rats. The (2R,6R)-HNK-induced potentiation occurred independent of N-methyl-D-aspartate receptor (NMDAR) activity, was accompanied by a concentration-dependent decrease in paired pulse ratios, and was occluded by raising glutamate release probability. In additon, in the presence of tetrodotoxin, (2R,6R)-HNK increased the frequency, but not amplitude, of mEPSC events, confirming a presynaptic site of action that is independent of glutamatergic network disinhibition. A dual extracellular recording configuration revealed that the presynaptic effects of (2R,6R)-HNK were synapse-selective, occurring in CA1-projecting SC terminals, but not in CA1-projecting temporoammonic terminals. Overall, we found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration-dependent, NMDAR-independent, and synapse-selective increase in glutamate release probability with no direct actions on AMPAR function. These findings provide novel insight regarding (2R,6R)-HNK’s acute mechanism of action, and may inform novel antidepressant drug mechanisms that could yield superior efficacy, safety, and tolerability.

Humans and nonhuman primates are vulnerable to age- and menopause-related decline in working memory, a cognitive function reliant on the energy-demanding recurrent excitation of neurons within Brodmann’s Area 46 of the dorsolateral prefrontal cortex (dlPFC). Here, we tested the hypothesis that the number and morphology (straight, curved, or donut-shaped) of mitochondria in dlPFC presynaptic boutons are altered with aging and menopause in rhesus monkeys (Macaca mulatta) and that these metrics correlate with delayed response (DR) accuracy, a well-characterized measure of dlPFC-dependent working memory. Although presynaptic bouton density or size was not significantly different across groups distinguished by age or menses status, DR accuracy correlated positively with the number of total and straight mitochondria per dlPFC bouton. In contrast, DR accuracy correlated inversely with the frequency of boutons containing donut-shaped mitochondria, which exhibited smaller active zone areas and fewer docked synaptic vesicles than those with straight or curved mitochondria. We then examined the effects of estrogen administration to test whether a treatment known to improve working memory influences mitochondrial morphology. Aged ovariectomized monkeys treated with vehicle displayed significant working memory impairment and a concomitant 44% increase in presynaptic donut-shaped mitochondria, both of which were reversed with cyclic estradiol treatment. Together, our data suggest that hormone replacement therapy may benefit cognitive aging, in part by promoting mitochondrial and synaptic health in the dlPFC.

Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca2+influx without significantly altering the Ca2+sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca2+]idriven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca2+([Ca2+]ₑ). Lowering external Ca2+to match the isoflurane-induced reduction in Ca2+entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca2+entry without significant direct effects on Ca2+-exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca2+influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system.

Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role in synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as a tool to describe the physiological role of cholesterol in glutamatergic synaptic transmission. Cholesterol proved to be a key molecule for the function of synapses as its depletion resulted in a significant reduction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents (eEPSCs), by 94% and 72%, respectively. We identified two presynaptic and two postsynaptic steps of synaptic transmission which are modulated by cholesterol and explain together the above-mentioned reduction of eEPSCs. In the postsynapse, we show that physiological levels of cholesterol are important for maintaining the normal probability of opening of NMDARs and for keeping NMDARs localized in synapses. In the presynapse, our results favour the hypothesis of a role of cholesterol in the propagation of axonal action potentials. Finally, cholesterol is a negative modulator of spontaneous presynaptic glutamate release. Our study identifies cholesterol as an important endogenous regulator of synaptic transmission and provides insight into molecular mechanisms underlying the neurological manifestation of diseases associated with impaired cholesterol synthesis or decomposition.