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The time course of DOR action on GABA release differs between CA1 and CA2. A, Sample traces of spontaneous IPSCs recorded in a CA2 pyramidal neuron before, during the application, and after the washout of 0.5 M DPDPE. B, Histograms summarizing the effect of DPDPE on sIPSC frequency and amplitude in CA2 PCs from control and DOR KO mice and for control mice in CA1 (n 8 for CA2 controls, n 4 for CA2 DOR KO and n 4 for CA1). C, Single example experiment showing the time course of the effect of DPDPE on miniature IPSCs frequency in CA2 and CA1 pyramidal neurons. Whereas mIPSC frequency is decreased following washout of DPDPE in CA2, a complete recovery of mIPSC frequency is observed in CA1. Dashed line marks average baseline frequency. D, Summary histograms of the effect of DPDPE on mIPSC frequency and amplitude in CA1 and CA2 pyramidal neurons (n 5 for CA2 and for CA1). *p 0.05, **p 0.01, ***p 0.001. Error bars show SEM.
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Inhibition is critical for controlling information transfer in the brain. However, the understanding of the plasticity and particular function of different interneuron subtypes is just emerging. Using acute hippocampal slices prepared from adult mice, we report that in area CA2 of the hippocampus, a powerful inhibitory transmission is acting as a g...
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... further examine the presynaptic site of action of DOR activation, we tested the effect of DPDPE on spontaneous IPSCs (sIPSCs). We found that DPDPE induced a significant decrease in sIPSC frequency. This effect was observed at the end of DPDPE application and 20 -25 min after DPDPE washout (Fig. 7 A, B; 69.1 4.0% at the end of DPDPE, p 0.00013, 77.6 5.3% after washout, p 0.0039, n 8). Conversely, DPDPE had no effect on sIPSC amplitude (Fig. 7B; 98.6 6.4% at the end of DPDPE, p 0.82, 102.15 6.4% after washout, p 0.74). We confirmed that this effect on sIPSC frequency was mediated by DOR activa- tion, as it was absent in DOR KO mice ( ...
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... 7 A, B; 69.1 4.0% at the end of DPDPE, p 0.00013, 77.6 5.3% after washout, p 0.0039, n 8). Conversely, DPDPE had no effect on sIPSC amplitude (Fig. 7B; 98.6 6.4% at the end of DPDPE, p 0.82, 102.15 6.4% after washout, p 0.74). We confirmed that this effect on sIPSC frequency was mediated by DOR activa- tion, as it was absent in DOR KO mice ( Fig. 7B; 101.08 3.9% at the end of DPDPE, p 0.79 and 104.2 1.9% after washout, p 0.12, n 4). Interestingly, whereas DPDPE also decreased sIPSC frequency in CA1 pyramidal neurons, this effect was transient and fully reversed following washout of DPDPE ( Fig. 7B; 76.9 5.3% at the end of DPDPE, p 0.023 and 102.4 3.8% after washout, p 0.57, n ...
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... effect on sIPSC frequency was mediated by DOR activa- tion, as it was absent in DOR KO mice ( Fig. 7B; 101.08 3.9% at the end of DPDPE, p 0.79 and 104.2 1.9% after washout, p 0.12, n 4). Interestingly, whereas DPDPE also decreased sIPSC frequency in CA1 pyramidal neurons, this effect was transient and fully reversed following washout of DPDPE ( Fig. 7B; 76.9 5.3% at the end of DPDPE, p 0.023 and 102.4 3.8% after washout, p 0.57, n ...
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... address whether DOR activation acts on GABA release downstream of Ca 2 influx, we tested the effect of DPDPE on the action-potential independent miniature IPSCs (mIPSCs). We found that DPDPE application induced a lasting decrease in CA2 mIPSC frequency without affecting mIPSC amplitude (Fig. 7C,D; for mIPSC frequency: 59.8 6.3% at the end of DPDPE, p 0.003 and 65.2 7.1% after washout, p 0.008, n 5; for mIPSC amplitude: 103.4 2.4% at the end of DPDPE, p 0.22 and 102.5 4.3% after washout, p 0.58, n 5). Consistently, the action of DPDPE on CA1 mIPSC frequency was transient ( Fig. 7C,D; for mIPSC frequency: 67.8 10.5% at the end of ...
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... in CA2 mIPSC frequency without affecting mIPSC amplitude (Fig. 7C,D; for mIPSC frequency: 59.8 6.3% at the end of DPDPE, p 0.003 and 65.2 7.1% after washout, p 0.008, n 5; for mIPSC amplitude: 103.4 2.4% at the end of DPDPE, p 0.22 and 102.5 4.3% after washout, p 0.58, n 5). Consistently, the action of DPDPE on CA1 mIPSC frequency was transient ( Fig. 7C,D; for mIPSC frequency: 67.8 10.5% at the end of DPDPE, p 0.038 and 95.1 5.9% after washout, p 0.46, n 5; for mIPSC amplitude: 100.3 5.4% at the end of DPDPE, p 0.95 and 106.7 4.9% after washout, p 0.24, n 5). From these results, we conclude that DORs are activated presynapti- cally on interneurons and are potentially reducing GABA ...
Citations
... Long-term depression is a type of plasticity unique to the hippocampal CA2 region [88]. This type of plasticity depends on maturation of PV interneurons during adolescence, mainly due to receptor tyrosineprotein kinase ErbB4 signaling and the formation of perineuronal nets around PV interneurons [84]. ...
... Various neuromodulators are involved in social coding. Activation of delta-opioid and cannabinoid type 1 receptors induces long-term depression of inhibitory transmission in the CA2, which is required for social memory formation [88,89]. Furthermore, oxytocinergic signalization modulates both excitatory pyramidal cells and PV interneurons in the CA2 [90]. ...
Finding a cure for Alzheimer’s disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.
... GABAergic Marker Brain Region κ-opioid receptors Glutamate decarboxylase [91] Hippocampus [92] κ-opioid receptors Calretinin [93] Dorsal striatum [93] κ-opioid receptors Parvalbumin [94] Basolateral amygdala [94] δ-opioid receptors Somatostatin [95] Dentate gyrus [95] δ-opioid receptors Parvalbumin [96] Hippocampal CA1 [96] δ-opioid receptors Parvalbumin [97] Hippocampal CA2 [97] ...
... GABAergic Marker Brain Region κ-opioid receptors Glutamate decarboxylase [91] Hippocampus [92] κ-opioid receptors Calretinin [93] Dorsal striatum [93] κ-opioid receptors Parvalbumin [94] Basolateral amygdala [94] δ-opioid receptors Somatostatin [95] Dentate gyrus [95] δ-opioid receptors Parvalbumin [96] Hippocampal CA1 [96] δ-opioid receptors Parvalbumin [97] Hippocampal CA2 [97] ...
... CA2, as the crucial subregion of the hippocampus for social behavior and novel memories, is not exempt from opioidergic modulation. DORs presynaptically induce LTD at the PV-expressing type of FSI innervating solely to the CA1 pyramidal neurons and short-term depression in the CA1 pyramidal neurons [97]. In the CA3 region, MORs mediate the disinhibition of GABA transmission (Table 1), which increases the net inhibitory activity, although DORs and KORs do not contribute to this mechanism [106,135]. ...
The functional interplay between the corticolimbic GABAergic and opioidergic systems plays a crucial role in regulating the reward system and cognitive aspects of motivational behaviors leading to the development of addictive behaviors and disorders. This review provides a summary of the shared mechanisms of GABAergic and opioidergic transmission, which modulate the activity of dopaminergic neurons located in the ventral tegmental area (VTA), the central hub of the reward mechanisms. This review comprehensively covers the neuroanatomical and neurobiological aspects of corticolimbic inhibitory neurons that express opioid receptors, which act as modulators of corticolimbic GABAergic transmission. The presence of opioid and GABA receptors on the same neurons allows for the modulation of the activity of dopaminergic neurons in the ventral tegmental area, which plays a key role in the reward mechanisms of the brain. This colocalization of receptors and their immunochemical markers can provide a comprehensive understanding for clinicians and researchers, revealing the neuronal circuits that contribute to the reward system. Moreover, this review highlights the importance of GABAergic transmission-induced neuroplasticity under the modulation of opioid receptors. It discusses their interactive role in reinforcement learning, network oscillation, aversive behaviors, and local feedback or feedforward inhibitions in reward mechanisms. Understanding the shared mechanisms of these systems may lead to the development of new therapeutic approaches for addiction, reward-related disorders, and drug-induced cognitive impairment.
... This study demonstrated that the density of both PV+ and Reelin-positive neurons were highest in Stratum oriens (so) of CA2, and that PV+, Reelin+ and Calbindin+ cells were the highest density in Stratum pyramidale (sp), as compared to areas CA3 and CA1. The high density of PV+ cells bodies in sp and so was also observed in mice using RGS14 staining as a boundary to define CA2 (Piskorowski and Chevaleyre, 2013). The morphology and physiological properties of GABAergic cells in area CA2 is vastly understudied as compared to CA1, where there are at least 21 different types of interneurons (Klausberger and Somogyi, 2008). ...
... The DOR-mediated iLTD that occurs in hippocampal area CA2 is specific to a subset of PV+ inhibitory neurons (Piskorowski and Chevaleyre, 2013). This was determined by selective expression of channelrhodopsin in PV+ interneuron and using light to evoke an inhibitory synaptic current while recording from CA2 pyramidal cells in voltage clamp mode. ...
... Inhibition of PV+ cells by CNO application entirely prevented induction of DOR-iLTD (Nasrallah et al., 2019). The DOR-iLTD is entirely pre-synaptic, with activation of the receptors resulting in reduced GABA release (Piskorowski and Chevaleyre, 2013). There is evidence that the resulting decrease in GABA release probability also depends on a trans-synaptic signaling between pyramidal neurons and PV+ interneurons through activation of the ErbB4 receptor located on PV+ terminals by Neuregulin 1 (Domínguez et al., 2019). ...
Hippocampal area CA2 plays a critical role in social recognition memory and has unique cellular and molecular properties that distinguish it from areas CA1 and CA3. In addition to having a particularly high density of interneurons, the inhibitory transmission in this region displays two distinct forms of long-term synaptic plasticity. Early studies on human hippocampal tissue have reported unique alteration in area CA2 with several pathologies and psychiatric disorders. In this review, we present recent studies revealing changes in inhibitory transmission and plasticity of area CA2 in mouse models of multiple sclerosis, autism spectrum disorder, Alzheimer’s disease, schizophrenia and the 22q11.2 deletion syndrome and propose how these changes could underly deficits in social cognition observed during these pathologies.
... The importance of hippocampal δOR activity in relation to convulsions has long been recognized. Research throughout the 1980s and 1990s have shown enkephalins are present within the hippocampus and the δORs themselves are expressed throughout the region (Chu Sin Chung and Kieffer, 2013;Erbs et al., 2012;Piskorowski and Chevaleyre, 2013). Microinjection of the δOR agonists such as Ala-deltorphin, DADLE, DSLET and SNC80 specifically in the hippocampus caused a variety of seizure responses, including wet-dog shakes, tremors, convulsions, EEG and ECoG epileptic-like abnormalities (De Sarro et al., 1992;Haffmans and Dzoljic, 1983;Lee et al., 1989;Sakamoto et al., 2021), suggesting this is a causative region regarding this behavior. ...
... Within the CA1, δOR expression is most concentrated in the stratum pyramidale (Svoboda et al., 1999). δORs are also present on CA2 and CA3 neurons and hilus of the dentate gyrus Faget et al., 2012;Piskorowski and Chevaleyre, 2013;Reeves et al., 2022). ...
The δ opioid receptor (δOR) is a therapeutic target for the treatment of various neurological disorders, such as migraines, chronic pain, alcohol use, and mood disorders. Relative to μ opioid receptor agonists, δOR agonists show lower abuse liability and may be potentially safer analgesic alternatives. However, currently no δOR agonists are approved for clinical use. A small number of δOR agonists reached Phase II trials, but ultimately failed to progress due to lack of efficacy. One side effect of δOR agonism that remains poorly understood is the ability of δOR agonists to produce seizures. The lack of a clear mechanism of action is partly driven by the fact that δOR agonists range in their propensity to induce seizure behavior, with multiple δOR agonists reportedly not causing seizures. There is a significant gap in our current understanding of why certain δOR agonists are more likely to induce seizures, and what signal-transduction pathway and/or brain area is engaged to produce these seizures. In this review we provide a comprehensive overview of the current state of knowledge of δOR agonist-mediated seizures. The review was structured to highlight which agonists produce seizures, which brain regions have been implicated and which signaling mediators have been examined in this behavior. Our hope is that this review will spur future studies that are carefully designed and aimed to solve the question why certain δOR agonists are seizurogenic. Obtaining such insight may expedite the development of novel δOR clinical candidates without the risk of inducing seizures.
... In addition, CA3-CA2 synapses are feedforward inhibited by parvalbumin expressing interneuron in the CA2 area (Leroy et al., 2017;Nasrallah et al., 2015Nasrallah et al., , 2019. This feedforward inhibitory transmission in area CA2 has an interesting synaptic plasticity that is delta opioid receptor dependent-long-term depression (iLTD) (Leroy et al., 2017;Nasrallah et al., 2015Nasrallah et al., , 2019Piskorowski & Chevaleyre, 2013). ...
The hippocampus is a center for spatial and episodic memory formation in rodents. Understanding the composition of subregions and circuitry maps of the hippocampus is essential for elucidating the mechanism of memory formation and recall. For decades, the trisynaptic circuit (entorhinal cortex layer II-dentate gyrus - CA3-CA1) has been considered the neural network substrate responsible for learning and memory. Recently, CA2 has emerged as an important area in the hippocampal circuitry, with distinct functions from those of CA3. In this article, we review the historical definition of the hippocampal area CA2 and the differential projection patterns between CA2 and CA3 pyramidal neurons. We provide a concise and comprehensive map of CA2 outputs by comparing (1) ipsi versus contra projections, (2) septal versus temporal projections, and (3) lamellar structures of CA2 and CA3 pyramidal neurons.
... allows CA2 PNs to be efficiently recruited by CA3 input, increasing synaptic drive onto CA1 (Nasrallah et al., 2015(Nasrallah et al., , 2019Piskorowski & Chevaleyre, 2013). This plasticity is entirely mediated by parvalbuminexpressing (PV+) interneurons (Nasrallah et al., 2019) and emerges during late-adolescence/early adulthood (Domínguez et al., 2019). ...
... We applied 0.5 μM of DPDPE ([D-Pen 2 ,D-Pen 5 ]Enkephalin, Tocris), an agonist for DORs. We have previously shown that this concentration effectively induces DOR-mediated iLTD in area CA2 and has no effect on inhibitory transmission in slices prepared from DOR knock-out mice (Piskorowski & Chevaleyre, 2013). We applied 5 μM N-(3-chlorophenyl)-6,-7-dimethoxy-4-quinazolinanine hydrochloride (AG1748, Tocris) as this concentration was used in previous studies to block the effect of NRG1 on GABA release via ErbB4 in both hippocampal and cortical slices (Chen et al., 2010;Domínguez et al., 2019;Woo et al., 2007). . ...
... From animals that had spent 3 weeks in SE, we observed a long-term depression of inhibitory transmission following a 100 Hz electrical stimulation of CA3 input. This plasticity is due to the activation of delta-opioid receptors and has previously been described (Piskorowski & Chevaleyre, 2013). In slices prepared from animals that had spent 3 weeks in EE, we observed a significant reduction in the amount of iLTD induced by the electrical stimulation ( Figure 1b; SE: 76.9 ± 4.1%, n = 8, p = 7.6 Â 10 À4 . ...
Environmental factors are well‐accepted to play a complex and interdependent role with genetic factors in learning and memory. The goal of this study was to examine how environmental conditions altered synaptic plasticity in hippocampal area CA2. To do this, we housed adult mice for 3 weeks in an enriched environment (EE) consisting of a larger cage with running wheel, and regularly changed toys, tunnels and treats. We then performed whole‐cell or extracellular field recordings in hippocampal area CA2 and compared the synaptic plasticity from EE‐housed mice with slices from littermate controls housed in standard environment (SE). We found that the inhibitory transmission recruited by CA3 input stimulation in CA2 was significantly less plastic in EE conditions as compared to SE following an electrical tetanus. We demonstrate that delta‐opioid receptor (DOR) mediated plasticity is reduced in EE conditions by direct application of DOR agonist. We show that in EE conditions the overall levels of GABA transmission is reduced in CA2 cells by analyzing inhibition of ErbB4 receptor, spontaneous inhibitory currents and paired‐pulse ratio. Furthermore, we report that the effect of EE of synaptic plasticity can be rapidly reversed by social isolation. These results demonstrate how the neurons in hippocampal area CA2 are sensitive to environment and may lead to promising therapeutic targets.
... First, SNC80-induced seizures have been linked to GABAergic neurons expressed in the forebrain (Chung et al., 2015), including the hippocampus. Second, the δOR is known to be expressed in the hippocampus and to mediate synaptic plasticity of hippocampal neurons (Valentino et al., 1982;Piskorowski and Chevaleyre, 2013;Erbs et al., 2014). . Quantification of phosphorylated ERK (pERK) over total ERK (ERK) all normalized to GAPDH as loading control. ...
The δ-opioid receptor (δOR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as δOR agonists are deemed safer alternatives relative to the more abuse-liable µ-opioid receptor drugs. Clinical development of δOR agonists, however, has been challenging in part due to the seizure-inducing effects of certain δOR agonists. Especially agonists that resemble the δOR-selective agonist SNC80 have well-established convulsive activity. Close inspection suggests that many of those seizurogenic δOR agonists efficaciously recruit β-arrestin, yet surprisingly, SNC80 displays enhanced seizure activity in β-arrestin 1 knockout mice. This finding led us to hypothesize that perhaps β-arrestin 1 is protective against, whereas β-arrestin 2 is detrimental for δOR-agonist-induced seizures. To investigate our hypothesis, we characterized three different δOR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and β-arrestin 1 and β-arrestin 2 knockout mice for seizure activity. We also investigated downstream kinases associated with β-arrestin-dependent signal transduction. We discovered that δOR agonist-induced seizure activity strongly and positively correlates with β-arrestin 2 efficacy for the agonist, but that indirect inhibition of ERK activation using the MEK inhibitor SL327 did not inhibit seizure potency and duration. Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in β-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that β-arrestin 2 is correlated with δOR agonist-induced seizure intensity, but that global β-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action.
... GABAergic Marker Brain Region κ-opioid receptors Glutamate decarboxylase [91] Hippocampus [92] κ-opioid receptors Calretinin [93] Dorsal striatum [93] κ-opioid receptors Parvalbumin [94] Basolateral amygdala [94] δ-opioid receptors Somatostatin [95] Dentate gyrus [95] δ-opioid receptors Parvalbumin [96] Hippocampal CA1 [96] δ-opioid receptors Parvalbumin [97] Hippocampal CA2 [97] ...
... GABAergic Marker Brain Region κ-opioid receptors Glutamate decarboxylase [91] Hippocampus [92] κ-opioid receptors Calretinin [93] Dorsal striatum [93] κ-opioid receptors Parvalbumin [94] Basolateral amygdala [94] δ-opioid receptors Somatostatin [95] Dentate gyrus [95] δ-opioid receptors Parvalbumin [96] Hippocampal CA1 [96] δ-opioid receptors Parvalbumin [97] Hippocampal CA2 [97] ...
... CA2, as the crucial subregion of the hippocampus for social behavior and novel memories, is not exempt from opioidergic modulation. DORs presynaptically induce LTD at the PV-expressing type of FSI innervating solely to the CA1 pyramidal neurons and short-term depression in the CA1 pyramidal neurons [97]. In the CA3 region, MORs mediate the disinhibition of GABA transmission (Table 1), which increases the net inhibitory activity, although DORs and KORs do not contribute to this mechanism [106,135]. ...
Tamoxifen-induced cognitive dysfunction may lead to fluoxetine consumption in patients with breast cancer. Since the brain mechanisms are unclear in tamoxifen/fluoxetine therapy, the blockade effect of hippocampal/amygdala/prefrontal cortical NMDA receptors was examined in fluoxetine/tamoxifen-induced memory retrieval. We also assessed the corticolimbic signaling pathways in memory retrieval under the drug treatment in adult male Wistar rats. Using the Western blot technique, the expression levels of the cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and cFos were evaluated in the corticolimbic regions. The results showed that pre-test administration of fluoxetine (3 and 5 mg/kg, i.p.) improved tamoxifen-induced memory impairment in the passive avoidance learning task. Pre-test bilateral microinjection of D-AP5, a selective NMDA receptor antagonist, into the dorsal hippocampal CA1 regions and the central amygdala (CeA), but not the medial prefrontal cortex (mPFC), inhibited the improving effect of fluoxetine on tamoxifen response. It is important to note that the microinjection of D-AP5 into the different sites by itself did not affect memory retrieval. Memory retrieval increased the signaling pathway of pCREB/CREB/BDNF/cFos in the corticolimbic regions. Tamoxifen-induced memory impairment decreased the hippocampal/PFC BDNF level and the amygdala level of pCREB/CREB/cFos. The improving effect of fluoxetine on tamoxifen significantly increased the hippocampal/PFC expression levels of BDNF, the PFC/amygdala expression levels of cFos, and the ratio of pCREB/CREB in all targeted areas. Thus, NMDA receptors’ activity in the different corticolimbic regions mediates fluoxetine/tamoxifen memory retrieval. The corticolimbic synaptic plasticity changes likely accompany the improving effect of fluoxetine on tamoxifen response.
... One possible explanation for these findings is that CB1R plasticity may require CA2 PNs to fire action potentials (APs) for induction. Indeed, CA3 inputs do not evoke APs in CA2 PNs in basal conditions (Piskorowski and Chevaleyre, 2013b), but they do following DOR-iLTD (Nasrallah et al., 2015). ...
Area CA2 is a critical region for diverse hippocampal functions including social recognition memory. This region has unique properties and connectivity. Notably, intra-hippocampal excitatory inputs to CA2 lack canonical long-term plasticity, but inhibitory transmission expresses a long-term depression mediated by Delta-opioid receptors (DOR-iLTDs). Evidence indicates that DOR-iLTDs are insufficient to underlie social coding. Here, we report a novel inhibitory plasticity mediated by cannabinoid type 1 receptor activation (CB1R-iLTD). Surprisingly, CB1R-iLTD requires previous induction of DOR-iLTDs, indicating a permissive role for DOR plasticity. Blockade of CB1Rs in CA2 completely prevents social memory formation. Furthermore, the sequentiality of DOR- and CB1R-mediated plasticity occurs in vivo during successive social interactions. Finally, CB1R-iLTD is altered in a mouse model of schizophrenia with impaired social cognition but is rescued by a manipulation that also rescues social memory. Altogether, our data reveal a unique interplay between two inhibitory plasticities and a novel mechanism for social memory formation.
... KOR and DOR activation in CA2 increases the PS following stratum radiatum stimulation (Vidal et al., 1984). Presynaptic DORs produce GABAergic LTD at FSI PV-expressing basket cell inputs to pyramidal neurons of CA2, but only short-term depression in CA1 (Piskorowski and Chevaleyre, 2013). The DOR effects enable long-lasting potentiation of CA2 transmission following high frequency stimulation of Schaffer collateral inputs that prevents the strong feedforward inhibition of CA3-CA2 transmission through DOR-mediated inhibitory LTD (iLTD) (Nasrallah et al., 2015). ...
Opioids mediate their effects via opioid receptors: mu, delta, and kappa. At the neuronal level, opioid receptors are generally inhibitory, presynaptically reducing neurotransmitter release and postsynaptically hyperpolarizing neurons. However, opioid receptor-mediated regulation of neuronal function and synaptic transmission is not uniform in expression pattern and mechanism across the brain. The localization of receptors within specific cell types and neurocircuits determine the effects that endogenous and exogenous opioids have on brain function. In this review we will explore the similarities and differences in opioid receptor-mediated regulation of neurotransmission across different brain regions. We discuss how future studies can consider potential cell-type, regional, and neural pathway-specific effects of opioid receptors in order to better understand how opioid receptors modulate brain function.
