Distribution of AMPA receptor subunit glur1 in the bed nucleus of the stria terminalis and effect of stress

The brain circuitry thought to be involved in stress responses includes several nuclei of the extended amygdala. The bed nucleus of the stria terminalis (BNST) is thought to be involved in the generation of sustained, nonspecific anxiety. Previous behavioral and electrophysiological experiments demonstrate that glutamate systems are involved in anxiety‐like behaviors in the BNST. Antagonists for AMPA receptors injected into the BNST decrease anxiety‐like behaviors. However, little is known about the role of AMPA receptors and the mechanism by which they act in the establishment of anxiety‐like behavior in response to a stressor. We hypothesized that the distribution of AMPA receptors is changed following a paradigm of unpredictable footshock as has been seen in the basolateral amygdala (BLA). We examined the subcellular localization of the GluR1 subunits of the AMPA receptor. We found that the neuropil of the BNST had a lower density of dendritic spines compared to dendritic shafts in the BLA. The majority of elements immunolabeled for GluR1 were dendritic shafts and spines with axonal and glial elements rarely labeled. Compared with controls, no significant effect was observed on days 1, 6, or 14 poststress. However, there was a trend for an increase at 6 and 14 days poststress. These data demonstrate that GluR1 subunits are primarily located on postsynaptic elements in the BNST. Moreover, it was shown that the response of the AMPA GluR1 subunit does not undergo a significant migration into spines from dendrites in response to a stressor as has been demonstrated in the BLA. Synapse 68:194–201, 2014 . Published 2014     

Glutamate inhibits thalamic reticular neurons.

Activation of metabotropic glutamate receptors (mGluRs) can result in long-lasting modulation of neuronal excitability. Multiple mGluR subtypes are localized within the rat thalamic reticular nucleus (TRN), and we have examined the effects of activating these different receptor subtypes on the excitability of these neurons using an in vitro slice preparation. Typical of most mGluR-sensitive preparations, the general mGluR agonist, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) produced a robust, long-lasting excitatory response. Surprisingly, ACPD produced a membrane hyperpolarization in some neurons. Using selective mGluR agonists, we found that activation of group II mGluRs produces the hyperpolarization, whereas the depolarization is mediated by group I mGluRs. While the polarity of the postsynaptic response (hyperpolarization vs depolarization) was dependent on the mGluR subtype activated, both actions appear to result from modification of a linear K(+) conductance. The inhibitory action of Glutamate, via group II mGluRs, provides an avenue for a disinhibitory effect that could have interesting consequences upon a well-investigated, model neuronal circuit, turning its assumed functional role upside down.     

Ultrastructural localization of cannabinoid CB1 and mGluR5 receptors in the prefrontal cortex and amygdala

Stimulation of the postsynaptic metabotropic glutamate receptor mGluR5 triggers retrograde signaling of endocannabinoids that activate presynaptic cannabinoid CB1 receptors on juxtaposing axon terminals. To better understand the synaptic structure that supports mGluR5 mediation of CB1 activation in the prefrontal cortex (PFC) and basolateral amygdala (BLA), we examined electron microscopic dual immunolabeling of these receptors in the prelimbic PFC (prPFC) and BLA of adult male rats. CB1 immunoreactivity was detected in axon terminals that were typically large, complex, and contained dense-core and clear synaptic vesicles. Of terminals forming discernible synaptic specializations, 95% were symmetric inhibitory-type in the prPFC and 90% were inhibitory in the BLA. CB1-immunoreactive terminals frequently contacted dendrites containing mGluR5 adjacent to unlabeled terminals forming excitatory-type synapses. Because most CB1-containing terminals form inhibitory-type synapses, the unlabeled axon terminals forming asymmetric synapses are the likely source of the mGluR5 ligand glutamate. In the prPFC, serial section analysis revealed that GABAergic CB1-containing axon terminals targeted dendrites adjacent to glutamatergic axon terminals, often near dendritic bifurcations. These observations provide ultrastructural evidence that cortical CB1 receptors are strategically positioned for integration of synaptic signaling in response to stimulation of postsynaptic mGluR5 receptors and facilitation of heterosynaptic communication between multiple neurons.     

The NMDA-NR1 receptor subunit and the mu-opioid receptor are expressed in somatodendritic compartments of central nucleus of the amygdala neurons projecting to the bed nucleus of the stria terminalis

The pathway between the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) is emerging as a critical mediator of stress-related affective processes. Evidence also indicates that exposure to drugs of abuse, like opioids, is associated with NMDA-type glutamate receptor-dependent plasticity in the CeA and BNST. However, there is little evidence that NMDA receptors are expressed in CeA neurons projecting to the BNST, or are required for opioid-induced BNST neural activation. Immunoelectron microscopy, tract tracing, and conditional gene deletion technology were used to investigate the synaptic organization of the NMDA receptor and the mu-opioid receptor (μOR) in the CeA-BNST pathway. By dual labeling electron microscopy, numerous CeA-BNST projection neurons expressed the NMDA-NR1 receptor subunit (NR1) or μOR. By triple labeling, it was also found that NR1 and μOR were co-expressed in some CeA-BNST projection neurons. Despite being colocalized in somato-dendritic compartments of CeA neurons, NR1 and μOR were rarely expressed in their axonal terminations in the BNST. Deleting the NR1 gene in CeA neurons resulted in a reduction of morphine-induced Fos protein labeling in the ventral BNST. In summary, NR1 and μOR are coexpressed in somatodendritic sites of CeA neurons, including those projecting to the BNST. In addition, expression of the NR1 gene in CeA neurons is required for morphine-induced BNST neural activation. Thus, postsynaptic NMDA receptors and μORs are positioned for the co-modulation of CeA projection neurons to the BNST, which may provide a synaptic substrate for stress-induced emotional processes critically involved in opioid addictive behaviors.     

Cocaine withdrawal reduces group I mGluR-mediated long-term potentiation via decreased GABAergic transmission in the amygdala

Cocaine relapse can occur when cocaine-associated environmental cues induce craving. Conditioned place preference (CPP) is a behavioral paradigm modeling the association between cocaine exposure and environmental cues. The amygdala is involved in cocaine cue associations with the basolateral amygdala (BLA) and central amygdala (CeA) acting differentially in cue-induced relapse. Activation of metabotropic glutamate receptors induces synaptic plasticity, the mechanism of which is thought to underlie learning, memory and drug-cue associations. The goal of this study was to examine the neural alterations in responses to group I metabotropic glutamate receptor (mGluR) agonists in the BLA to lateral capsula of CeA (BLA-CeLc) pathway in slices from rats exposed to cocaine-CPP conditioning and withdrawn for 14 days. mGluR1, but not mGluR5, agonist-induced long-term potentiation (mGluR1-LTP) in the BLA-CeLc pathway was reduced in rats withdrawal from cocaine for 2 and 14 days, and exhibited an altered concentration response to picrotoxin. Cocaine withdrawal also reduced γ-aminobutyric acid (GABA)ergic synaptic inhibition in CeLc neurons. Blocking cannabinoid receptor 1 (CB(1) ) reduced mGluR1-LTP in the saline-treated but not cocaine-withdrawn group. Response to CB(1) but not CB(2) agonist was altered after cocaine. Additionally, increasing endocannabinoid (eCB) levels abolished mGluR1-LTP in the saline but not cocaine-withdrawn group. However, CB(1) and CB(2) protein levels were increased in the amygdala of cocaine-withdrawn rats while mGluR1 and mGluR5 remained unchanged. These data suggested that the mechanisms underlying the diminished mGluR1-LTP in cocaine-withdrawn rats involve an altered GABAergic synaptic inhibition mediated by modulation of downstream eCB signaling. These changes may ultimately result in potentiated responses to environmental cues that would bias behavior toward drug-seeking.     

Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala

Increasing evidence indicates that excessive inflammatory responses play a crucial role in the pathophysiology of psychiatric diseases, including depression and anxiety disorders. The dysfunctional neural plasticity in amygdala has long been proposed as the vital cause for the progression of psychiatric disorders. However, the effect of neuroinflammation on the functional changes of the amygdala remains largely unknown. Here, by using a mouse model of inflammation induced by lipopolysaccharide (LPS) injection, we investigated the effect of LPS-induced neuroinflammation on the synaptic and non-synaptic plasticity in basolateral amygdala (BLA) projection neurons (PNs) and their contribution to the LPS-induced anxiety- and depressive-like behavior. The results showed that LPS treatment led to the activation of microglia and production of proinflammatory cytokines in the BLA. Furthermore, LPS treatment increased excitatory but not inhibitory synaptic transmission due to the enhanced presynaptic glutamate release, thus leading to the shift of excitatory/inhibitory balance towards excitatory. In addition, the intrinsic neuronal excitability of BLA PNs was also increased by LPS treatment through the loss of expression and function of small-conductance, calcium-activated potassium channel. Chronic fluoxetine pretreatment significantly prevented these neurophysiological changes induced by LPS, and alleviated anxiety and depressive-like behavior, indicating that LPS-induced neuronal dysregulation of BLA PNs may contribute to the development of psychiatry disorders. Collectively, these findings provide evidence that dysregulation of synaptic and non-synaptic transmission in the BLA PNs may account for neuroinflammation-induced anxiety- and depressive-like behavior.     

Metabotropic Glutamate Receptors in the Rat Nucleus Accumbens

The effects of glutamate metabotropic receptors (mGluRs) on excitatory transmission in the nucleus accumbens were investigated using electrophysiological techniques in rat nucleus accumbens slices. The broad-spectrum mGluR agonist (1S,3 R )-1-aminocyclopentyl-1,3-dicarboxylate, the mGluR group 2 selective agonists (S)-4-carboxy-3-hydroxyphenylglycine, (1S,3S)-ACPD) and (2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine (L-CCG1), and the mGluR group 3 specific agonist L-2-amino-4-phosphonobutyrate (L-AP4) all reversibly inhibited evoked excitatory synaptic responses. The specific group 1 mGluR agonist (R,S)-3,5-dihydroxyphenylglycine [(R,S)-DHPG] did not depress transmission. Dose-response curves showed that the rank order of agonist potencies was: L-CCGI > L-AP4 > (1 S,3S)-ACPD. Group 2 and 3 mGluRs inhibited transmission via a presynaptic mechanism, as they increased paired-pulse facilitation, decreased the frequency of miniature excitatory postsynaptic currents and had no effect on their amplitude. The mGluRs did not inhibit transmitter release by reducing voltage-dependent Ca²⁺ currents through N- or P-type Ca²⁺ channels, as inhibition persisted in the presence of a-conotoxin-GVIA or Aga-IVA. The depression induced by mGluRs was not affected by specific antagonists of dopamine D1, GABA-B or adenosine A1 receptors, indicating direct effects. Finally, (13,s)-DHPG specifically blocked the postsynaptic afterhyperpolarization current (I_ahp). Our results represent the first direct demonstration of functional mGluRs in the nucleus accumbens of the rat.     

Metabotropic Glutamate Receptors Inhibiting Excitatory Synapses in the CA1 Area of Rat Hippocampus

In the CA1 region of hippocampal slices prepared from young adult rats, we studied the ability of several specific agonists of metabotropic glutamate receptors (mGluRs) to depress excitatory synaptic transmission at the CA3–CA1 pyramidal cell synapses. Three groups of mGluRs have been described: group 1 (mGluR1 and 5) receptors are positively coupled to phospholipase C whereas group 2 (mGluR2 and 3) and group 3 (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenylate cyclase. We found that the broad-spectrum agonist (1 S ,3R)-1-aminocyclopentyl-1,3-dicarboxylate and the group 1-specific agonist ( R,S )-dihydroxyphenylglycine both reversibly inhibited evoked field excitatory postsynaptic potentials, indicating the involvement of group 1 mGluRs. ( R,S )-3,5-dihydroxyphenylglycine presumably inhibited transmission via a presynaptic mechanism, as whole-cell voltage-clamp recordings revealed that inhibition of the synaptic transmission was always accompanied with an increase in paired-pulse facilitation. Treatment with a specific blocker of mGluR1 receptors, the phenylglycine derivative ( S )-4-carboxyphenylglycine, was without effect on the (1 S ,3 R )-1-amino-cyclopentyl-1,3-dicarboxylate-induced depression of the field excitatory postsynaptic potentials, strongly suggesting that mGluR5 receptors are responsible for the (1 S ,3 R )-1-aminocyclopentyl-1,3-dicarboxylate effect. Two selective agonists of group 2 mGluRs, (2 S ,1' s ,2' s )-2-(2'-carboxycyclopropyl)glycine and 4-carboxy-3-hydroxyphenylglycine, were totally ineffective in blocking CA3-CA1-evoked synaptic transmission, excluding the involvement of mGluR2/3 subtypes at this developmental stage.     

Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving.

BACKGROUND: We and others reported time-dependent increases in cue-induced cocaine seeking after withdrawal, suggesting that craving incubates over time. Recently, we found that central amygdala extracellular signal-regulated kinases (ERK) and glutamate are involved in this incubation. Here, we further explored the role of central amygdala glutamate in the incubation of cocaine craving by determining the effect of systemic or central amygdala injections of the mGluR2/3 agonist LY379268 (which decreases glutamate release) on cue-induced cocaine seeking during early and late withdrawal. METHODS: Rats were trained to self-administer cocaine for 10 days (6 hours/day); infusions were paired with a tone-light cue. Cocaine seeking and craving after systemic or central amygdala injections of LY379268 were then assessed in extinction tests in the presence of the cocaine-associated cues during early (day 3) or late (day 21) withdrawal. RESULTS: Systemic (1.5 or 3 mg/kg) or central amygdala (.5 or 1.0 microg/side) injections of LY379268 attenuated enhanced extinction responding on day 21 but had no effect on lower extinction responding on day 3. CONCLUSIONS: Results confirm our previous findings on the role of central amygdala glutamate in the incubation of cocaine craving and together with previous reports suggest that mGluR(2/3) agonists should be considered in the treatment of drug relapse.     

Potentiation of synaptic strength and intrinsic excitability in the nucleus accumbens after 10 days of morphine withdrawal

Neuroadaptations in the nucleus accumbens (NAc) are associated with the development of drug addiction. Plasticity in synaptic strength and intrinsic excitability of NAc medium spiny neurons (MSNs) play critical roles in addiction induced by different classes of abused drugs. However, it is unknown whether morphine exposure influences synaptic strength, intrinsic excitability or both in NAc. Here we show that chronic withdrawal (10 days after the last injection) from repeated morphine exposure elicited potentiation in both glutamatergic synaptic strength and intrinsic excitability of MSNs in NAc shell (NAcSh). The potentiation of synaptic strength was demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), a decrease in the paired-pulse ratio (PPR), and an increase in the ratio of α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR)- to N-methyl-D-aspartate receptors (NMDAR)-mediated currents. The potentiation of intrinsic excitability was mediated by inhibition of the sustained potassium currents via extrasynaptic NMDAR activation. The function of the presynaptic group II metabotropic glutamate receptors (mGluR2/3) was downregulated, enhancing the probability of glutamate release on synaptic terminals during chronic morphine withdrawal. Pretreatment with the mGluR2/3 agonist LY379268 completely blocked potentiation of both synaptic strength and intrinsic excitability. These results suggest that chronic morphine withdrawal downregulates mGluR2/3 to induce potentiation of MSN glutamatergic synapse via increased glutamate release, leading to potentiation of intrinsic excitability. Such potentiation of both synaptic strength and intrinsic excitability might contribute to neuroadaptations induced by morphine application.     

Synaptic mechanisms of NMDA-mediated hyperpolarization in lateral amygdaloid projection neurons

Synaptic mechanisms underlying NMDA-mediated responses of neurons in the guinea pig lateral amygdala (AL) were investigated in in vitro slice preparations. Local application of NMDA resulted in initial hyperpolarization of pyramidal-like spiny cells (projection neurons), followed by prolonged depolarization. The slow depolarization represented a direct postsynaptic effect of NMDA, whereas the initial hyperpolarization was induced presynaptically through activation of GABAergic interneurons and was sensitive to blockade by tetrodotoxin as well as the GABA(A)-receptor antagonist bicuculline. Application of NMDA resulted in AP-5-sensitive, lasting depolarization also in putative interneurons of the AL suggesting direct activation of GABAergic interneurons by NMDA. These data indicate that interneurons in the rat lateral amygdala possess functional NMDA receptors, which may contribute to the predominantly inhibitory synaptic responses in amygdaloid neurons following activation through afferent input systems.     

Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist produces anxiolytic-like effects and reverses abnormal firing activity of projection neurons in the basolateral nucleus of the amygdala in rats with bilateral 6-OHDA lesions

Although 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 antagonist, improves the motor symptoms of Parkinson's disease (PD), the effects of MPEP on the psychiatric symptom of PD and the mechanism involved are still unclear. In the present study, we examined the effects of MPEP in anxiolytic-like behavior and firing activity of projection neurons in the basolateral nucleus of the amygdala (BLA) in rats with 6-hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum. Rats were divided into three groups, sham-operated group, 6-OHDA lesion with vehicle treatment group and 6-OHDA lesion with MPEP treatment group. Injection of 6-OHDA (10.5 μg) into the dorsal striatum produced 31.5% loss of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the SNpc. The 6-OHDA-lesioned rats showed anxiety behavior and the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and no difference was found in the firing pattern of these neurons. Whereas chronic, systemic treatment of MPEP (3 mg/kg/day, i.p.; 14 days) attenuated loss of TH-ir neurons, produced anxiolytic-like effect and normalized the abnormal firing rate of projection neurons of the BLA in rats with the bilateral lesions. Systemic administration of cumulative apomorphine (10-160 μg/kg, i.v.) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA lesion with vehicle-treated and MPEP-treated rats, but the 6-OHDA lesion decreased the response of BLA projection neurons to apomorphine stimulation, while MPEP reversed the reactivity of these neurons. These data demonstrate that the partial lesion of the nigrostriatal pathway causes anxiety symptom and decreases firing rate of BLA projection neurons in the rat. Furthermore, chronic, systemic MPEP treatment has the neuroprotective and anxiolytic-like effects, and reverses the abnormal firing rate of BLA projection neurons, suggesting that MPEP has important implication for the treatment of PD.     

Cortical Layer-specific Effects of the Metabotropic Glutamate Receptor Agonist 1S,3R-ACPD in Rat Primary Somatosensory Cortex In Vivo

The effects of iontophoretically applied (1 S ,3 R )-1-aminocyclopentane-1,3-dicarboxylic acid (1 S ,3 R -ACPD), a metabotropic glutamate receptor (mGluR) agonist, were studied on extracellularly recorded neurons throughout the depth of the primary somatosensory cortex in the anaesthetized adult rat. Distinct excitatory effects were found almost exclusively in neurons recorded in layer V. Postsynaptic depressant effects dominated neurons recorded in layers I–IV. In layer VI, neurons were equally divided as to excitation and depression. Both the excitatory and postsynaptic depressant effects could be antagonized by the mGluR antagonist ( RS ) - α-methyl-4-carboxyphenylglycine (MCPG). Experiments using bicuculline and several lines of analysis suggested that the postsynaptic depressant effects were mediated directly, rather than through disfacilitation. In a proportion of neurons 1 S ,3 R -ACPD selectively depressed synaptically evoked responses (produced by vibrissa deflections), with little or no effect on the postsynaptic level of firing. Comparing the depressant effects of 1 S ,3 R -ACPD with those of GABA supported a presynaptic mGluR site. Responses to centre and surround receptive field stimulation were depressed to the same extent, suggesting that thalamocortical and intracortical axon terminals are equally endowed with presynaptic receptors. In contrast to previous studies, the actions of l -2-amino-4-phosphonobutyric acid (L-AP4) were shown to be qualitatively different to those of 1 S ,3 R -ACPD, in particular suggesting that the presynaptic depression produced by 1 S ,3 R -ACPD is not mediated by l -AP4-type receptors. The functional implications of different mGluR actions in the primary somatosensory cortex are discussed.     

Favouring inhibitory synaptic drive mediated by GABAA receptors in the basolateral nucleus of the amygdala efficiently reduces pain symptoms in neuropathic mice

Pain is an emotion and neuropathic pain symptoms are modulated by supraspinal structures such as the amygdala. The central nucleus of the amygdala is often called the ‘nociceptive amygdala’, but little is known about the role of the basolateral amygdala. Here, we monitored the mechanical nociceptive thresholds in a mouse model of neuropathic pain and infused modulators of the glutamate/GABAergic transmission in the basolateral nucleus of the amygdala (BLA) via chronically‐implanted cannulas. We found that an N‐methyl‐D‐aspartate‐type glutamate receptor antagonist (MK‐801) exerted a potent antiallodynic effect, whereas a transient allodynia was induced after perfusion of bicuculline, a GABA_A receptor antagonist. Potentiating GABA_A receptor function using diazepam or etifoxine (a non‐benzodiazepine anxiolytic) fully but transiently alleviated mechanical allodynia. Interestingly, the antiallodynic effect of etifoxine disappeared in animals that were incapable of producing 3α‐steroids. Diazepam had a similar effect but of shorter duration. As indicated by patch‐clamp recordings of BLA neurons, these effects were mediated by a potentiation of GABA_A receptor‐mediated synaptic transmission. Together with a presynaptic elevation of miniature inhibitory postsynaptic current frequency, the duration and amplitude of GABA_A miniature inhibitory postsynaptic currents were also increased (postsynaptic effect). The analgesic contribution of endogenous neurosteroid seemed to be exclusively postsynaptic. This study highlights the importance of the BLA and the local inhibitory/excitatory neuronal network activity while setting the mechanical nociceptive threshold. Furthermore, it appears that promoting inhibition in this specific nucleus could fully alleviate pain symptoms. Therefore, the BLA could be a novel interesting target for the development of pharmacological or non‐pharmacological therapies.     

Functional and ultrastructural analysis of group I mGluR in striatal fast-spiking interneurons

Striatal parvalbumin-containing fast-spiking (FS) interneurons provide a powerful feedforward GABAergic inhibition on spiny projection neurons, through a widespread arborization and electrical coupling. Modulation of FS interneuron activity might therefore strongly affect striatal output. Metabotropic glutamate receptors (mGluRs) exert a modulatory action at various levels in the striatum. We performed electrophysiological recordings from a rat striatal slice preparation to investigate the effects of group I mGluR activation on both the intrinsic and synaptic properties of FS interneurons. Bath-application of the group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (3,5-DHPG), caused a dose-dependent depolarizing response. Both (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), selective mGluR1 antagonists, significantly reduced the amplitude of the membrane depolarization caused by 3,5-DHPG application. Conversely, mGluR5 antagonists, 2-methyl-6-(phenylethylnyl)pyridine hydrochloride (MPEP) and 6-methyl-2-(phenylazo)-3-pyridinol (SIB1757), were unable to affect the response to 3,5-DHPG, suggesting that only mGluR1 contributes to the 3,5-DHPG-mediated excitatory action on FS interneurons. Furthermore, mGluR1 blockade significantly decreased the amplitude of the glutamatergic postsynaptic potentials, whereas the mGluR5 antagonist application produced a small nonsignificant inhibitory effect. Surprisingly, our electron microscopic data demonstrate that the immunoreactivity for both mGluR1a and mGluR5 is expressed extrasynaptically on the plasma membrane of parvalbumin-immunoreactive dendrites of FS interneurons. Together, these results suggest that despite a common pattern of distribution, mGluR1 and mGluR5 exert distinct functions in the modulation of FS interneuron activity.     

Neurophysiology of limbic system pathways in the rat: Projections from the amygdala to the entorhinal cortex

We studied the responses of rat entorhinal neurons to electrical stimulation of the amygdala. Four main results were obtained: (1) excitatory postsynaptic potentials were recorded in entorhinal neurons in response to electrical stimulation of the amygdala. Cells in layers II, III and V of the entorhinal cortex were responsive. (2) Excitatory responses were followed by inhibitory postsynaptic potentials. (3) Frequency potentiation of both excitatory and inhibitory responses was observed when 10/s stimulation was used. (4) Three amygdala neurons were antidromically activated by entorhinal stimulation; and two layer II entorhinal cells that were excited by amygdala stimulation were also antidromically activated by dentate gyrus stimulation. These results provide evidence for a monosynaptic, excitatory projection from the amygdala to the entorhinal cortex. In addition, the data indicate that amygdala neurons are only one synapse removed from the excitation of dentate gyrus granule cells.     

Ionotropic and metabotropic glutamate receptors show unique postsynaptic,presynaptic, and glial localizations in the dorsal cochlear nucleus

The dorsal cochlear nucleus (DCN) is a major brain center for integration of auditory information, and excitatory amino acid neurotransmission plays a central role in the processing of this information. In this study, the distribution of glutamate receptors was examined with preembedding immunocytochemistry, using 14 antibodies to ionotropic (GluR1, GluR2/3, GluR4, GluR5-7, GluR6/7, KA2, NR1, NR2A/B, delta 1/2) and metabotropic (mGluR1α, mGluR2/3, mGluR5) glutamate receptor subtypes. Each of these antibodies produced a specific immunolabeling pattern, including a variety of postsynaptic, presynaptic, and glial localizations. Some antibodies showed widespread distribution patterns, notably the antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunits, GluR2 and GluR3, and the N-methyl-D-aspartate (NMDA) receptor subunit, NR1. In contrast, antibodies to other glutamate receptor subunits produced more restricted distribution patterns, especially that to GluR1, which stained the outer neuropil of the DCN, cartwheel cells, and a small population of presumptive interneurons associated with the dorsal acoustic stria, but produced little or no staining in fusiform cells or deep DCN neurons. Staining of the postsynaptic density and membrane of the granule cell-parallel fiber/cartwheel cell spine synapse was most prevalent with delta 1/2 and mGluR1α antibodies. A unique pattern of staining was found with mGluR2/3 antibody—with staining concentrated in Golgi cells and unipolar brush cells of the middle to deep DCN. Distribution of some glutamate receptors in the DCN shows similarities to that of the cerebellum, where delta 2 and mGluR1α may modulate neurotransmission at parallel fiber synapses, while mGluR2 and/or mGluR3 may modulate mossy terminal function. © 1996 Wiley-Liss, Inc.     

mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors

Excitatory glutamatergic synapses on dopamine (DA) neurons of the ventral tegmental area (VTA) undergo long-lasting changes during conditioning of natural rewards and in response to drug exposure. It has been suggested that the ensuing context-dependent behavioural changes are associated with an increased efficacy of synaptic afferents determined by the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the molecular nature of the forms of LTP/LTD involved remains elusive. Here, using acute rat brain slices, we describe a form of long-term depression (LTD) that was engaged by synaptic activity or exogenous agonists activating group I metabotropic glutamate receptors (mGluR) and was sensitive to mGluR1 antagonists. Prior to mGluR-LTD, AMPAR mediated excitatory postsynaptic currents (EPSCs) showed strong rectification at positive potentials and were sensitive to Joro spider toxin (JST), a selective blocker of GluR2-lacking AMPARs. After mGluR-LTD, AMPAR EPSCs had linear current-voltage relations and became insensitive to JST. We conclude that activation of mGluR1s triggers a redistribution exchanging native receptors for GluR2 containing AMPARs, ultimately causing LTD that may oppose pathological neuroadaptation.