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The Group III Metabotropic Receptor Agonist L-AP4 Depresses Monosynaptic IPSCs and EPSCs in Interneurons to the Same Extent (A) IPSC amplitude (mean SEM) normalized to the average amplitude prior to addition of L-AP4 (n 5). Sample traces (above) were obtained before, during, and after L-AP4 application in one neuron (averages of 30 trials). (B) EPSC amplitudes plotted in the same way in a separate series of experiments (n 5). (C) The depression of IPSCs is accompanied by a decrease in the statistic 1/CV 2 , implying a decrease in quantal content. The statistic 1/CV 2 was normalized to the baseline value in each cell before averaging across experiments and plotted against the IPSC amplitude, similarly normalized. The diagonal line shows the trajectory expected from a Poisson model, with a decrease in the release parameter m. (D) The L-AP4-induced depression is accompanied by a reversible decrease in pairedpulse depression, further implying a presynaptic site of action. The insets show averaged traces obtained before, during, and after L-AP4 application in one experiment. Thick lines show control and washout superimposed; thin lines show L-AP4. The traces at right were normalized to set the peak amplitude of the first IPSC constant, showing the attenuation of paired-pulse depression (*p 0.05).
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Synapses between hippocampal interneurons are an important potential target for modulatory influences that could affect overall network behavior. We report that the selective group III metabotropic receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depresses GABAergic transmission to interneurons more than to pyramidal neurons. The L-AP4...
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Long term depression (LTD) in the CA1 region of the hippocampus, induced with a 20-Hz, 30 s tetanus to Schaffer collaterals, is enhanced in sleep-deprived (SD) rats. In the present study, we investigated the role of metabotropic glutamate receptors (mGluRs), γ-aminobutyric acid (GABA) B receptors (GABA(B)-Rs) and N-methyl-D-aspartic acid receptors...
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... This vasoconstrictive effect could transiently reduce blood flow to the activated brain region, potentially shortening the duration of the hemodynamic response (reflected in a shorter FWHM). Depending on the specific receptor subtype activated, serotonin may also enhance or inhibit synaptic transmission, affecting the duration and magnitude of neural activity within the neurovascular unit 43 . Therefore, increased platelet reactivity and platelet serotonin release might lead to dysregulated neurotransmission and vascular tone regulation within the neurovascular unit. ...
Platelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as athero-thrombosis 1,2 . Elevated haemostatic markers are linked to dementia ³ and predict its onset in long-term studies ⁴ . Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and neurovascular function in 52 healthy mid- to older-age adults. To do this, we combined, for the first time, magnetic resonance imaging (MRI) of neurovascular function, peripheral vascular physiology, and in vitro platelet assaying. We show a direct association between platelet reactivity and neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (Adenosine 5’-diphosphate, Collagen-Related Peptide, Thrombin Receptor Activator Peptide 6) were directly associated with different physiological components of the haemodynamic response to neural (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Since altered neurovascular function marks the initial stages of neurodegenerative pathophysiology ⁵ , understanding this novel association becomes now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology.
... One of the key pathways in the tripartite synapse is mediated by glutamate released by the astrocyte [32][33][34] . Such glutamate can potentially target presynaptic NMDA receptors, which increase the release probability 35 , or presynaptic mGluRs, which decrease it 36 . Presynaptic kainate receptors exhibit a more complex modulation of synaptic transmission through both metabotropic and ionotropic effects 37,38 . ...
Coherent activations of brain neuron networks underlie many physiological functions associated with various behavioral states. These synchronous fluctuations in the electrical activity of the brain are also referred to as brain rhythms. At the cellular level, rhythmicity can be induced by various mechanisms of intrinsic oscillations in neurons or the network circulation of excitation between synaptically coupled neurons. One specific mechanism concerns the activity of brain astrocytes that accompany neurons and can coherently modulate synaptic contacts of neighboring neurons, synchronizing their activity. Recent studies have shown that coronavirus infection (Covid-19), which enters the central nervous system and infects astrocytes, can cause various metabolic disorders. Specifically, Covid-19 can depress the synthesis of astrocytic glutamate and gamma-aminobutyric acid. It is also known that in the post-Covid state, patients may suffer from symptoms of anxiety and impaired cognitive functions. We propose a mathematical model of a spiking neuron network accompanied by astrocytes capable of generating quasi-synchronous rhythmic bursting discharges. The model predicts that if the release of glutamate is depressed, normal burst rhythmicity will suffer dramatically. Interestingly, in some cases, the failure of network coherence may be intermittent, with intervals of normal rhythmicity, or the synchronization can disappear.
... One of the key pathways in the tripartite synapse is mediated by glutamate released by the astrocyte [25][26][27] . Such glutamate can potentially target presynaptic NMDA receptors, which increase the release probability 28 , or presynaptic mGluRs, which decrease it 29 . Presynaptic kainate receptors exhibit a more complex modulation of synaptic transmission through both metabotropic and ionotropic effects 30,31 . ...
Coherent activations of brain neuron networks underlay many physiological functions associated with various behavioral states. These synchronous fluctuations in the electrical activity of the brain are also referred to as brain rhythms. At the cellular level, the rhythmicity can be induced by various mechanisms of intrinsic oscillations in neurons or network circulation of excitation between synaptically coupled neurons. One of the specific mechanisms concerns the activity of brain astrocytes that accompany neurons and can coherently modulate synaptic contacts of neighboring neurons, synchronizing their activity. Recent studies have shown that coronavirus infection (Covid-19), entering the central nervous system and infecting astrocytes, causes various metabolic disorders. Specifically, Covid-19 can depress the synthesis of astrocytic glutamate and GABA. It is also known that in the postcovid state, patients may suffer from symptoms of anxiety and impaired cognitive functions, which may be a consequence of disturbed brain rhythms. We propose a mathematical model of a spiking neural network accompanied by astrocytes capable to generate quasi-synchronous rhythmic bursting discharges. The model predicts that if the astrocytes are infected, and the release of glutamate is depressed, then normal burst rhythmicity suffers dramatically. Interestingly, in some cases, the failure of network coherence may be intermittent with intervals of normal rhythmicity, or the synchronization can completely disappears.
... In addition to its ability to regulate glutamate release, L-AP4 has been found to reduce inhibitory transmission in many brain regions, including the midbrain, globus pallidus, striatum, thalamus, and hippocampus (Mercier and Lodge, 2014). Importantly, hippocampal electrophysiological studies bolstered evidence for the localization of group III mGlu receptors on both glutamate and GABA terminals, such that L-AP4 has reduced both excitatory and inhibitory transmission onto hippocampal interneurons and pyramidal cells (Semyanov and Kullmann, 2000;Kogo et al., 2004;Klar et al., 2015). The critical role of group III mGlu receptors on interneurons highlights their utility in regulating the balance of excitation and inhibition of these cells, thus regulating overall network excitability (Ferraguti and Shigemoto, 2006;Klar et al., 2015). ...
Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders.
Significance Statement
Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.
... We have also tested if synaptic inputs to the 2 distinct cell types differed in their regulation by glutamate receptors. We chose to study group III metabotropic glutamate receptors (mGluRs), because of previous indications from studies on rodents that group III mGluRs are differentially expressed in cortical GABAergic neurons (Dalezios et al. 2002;Somogyi et al. 2003) and selectively regulate GABAergic synaptic transmission (Semyanov and Kullmann 2000;Kogo et al. 2004;Klar et al. 2015), and because of the large investment into developing drugs acting on group III mGluRs for the treatment of neurological and psychiatric conditions (Maksymetz et al. 2017;Charvin 2018;Ferraguti 2018). The results presented here, some of which have been published in abstract form (Lukacs et al. , 2020, reveal a high degree of multidimensional specialization of human GABAergic interneurons. ...
... Bars: mean, whiskers: one standard deviation, line: median, number of boutons are indicated, individual data points are shown. interneuron and pyramidal cells (Semyanov and Kullmann 2000;Kogo et al. 2004). However, neither the subcellular localisation nor the functions of group III mGluRs are known in the human neocortex. ...
... Conversely, normalized change in sIPSC amplitude in DBCs and PV-DTCs did not differ from the change in vehicle-treated controls (Fig. 9n, Kruskal-Wallis test, P = 0.382). These comparisons show that L-AP4 alters the frequency rather than on the amplitude of sIPSCs, which indicates that L-AP4 primarily acts through modulation of neurotransmitter release at the level of axon terminals, in accordance with previous studies in rodents (Gerber et al. 2000;Semyanov and Kullmann 2000;Matsui and Kita 2003;Drew and Vaughan 2004;Kogo et al. 2004;Cuomo et al. 2009). However, in our experiments, APs and fast glutamatergic synaptic transmission were not blocked, thus such conclusions could not be drawn, and the unexpected increase of sIPSC frequency in DBCs is likely the result of a complex network effect, by group III mGluRs acting at both GABAergic and glutamatergic synapses and multiple levels of synaptic connections, resulting in the disinhibition of a GABAergic synaptic input specific to DBCs. ...
Diverse neocortical GABAergic neurons specialize in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABA A receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in 2 distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBCs) had columnar "horsetail" axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and nonpyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%), and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline) but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialized, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.
... We have also tested if synaptic inputs to the 2 distinct cell types differed in their regulation by glutamate receptors. We chose to study group III metabotropic glutamate receptors (mGluRs), because of previous indications from studies on rodents that group III mGluRs are differentially expressed in cortical GABAergic neurons (Dalezios et al. 2002;Somogyi et al. 2003) and selectively regulate GABAergic synaptic transmission (Semyanov and Kullmann 2000;Kogo et al. 2004;Klar et al. 2015), and because of the large investment into developing drugs acting on group III mGluRs for the treatment of neurological and psychiatric conditions (Maksymetz et al. 2017;Charvin 2018;Ferraguti 2018). The results presented here, some of which have been published in abstract form (Lukacs et al. , 2020, reveal a high degree of multidimensional specialization of human GABAergic interneurons. ...
... Bars: mean, whiskers: one standard deviation, line: median, number of boutons are indicated, individual data points are shown. interneuron and pyramidal cells (Semyanov and Kullmann 2000;Kogo et al. 2004). However, neither the subcellular localisation nor the functions of group III mGluRs are known in the human neocortex. ...
... Conversely, normalized change in sIPSC amplitude in DBCs and PV-DTCs did not differ from the change in vehicle-treated controls (Fig. 9n, Kruskal-Wallis test, P = 0.382). These comparisons show that L-AP4 alters the frequency rather than on the amplitude of sIPSCs, which indicates that L-AP4 primarily acts through modulation of neurotransmitter release at the level of axon terminals, in accordance with previous studies in rodents (Gerber et al. 2000;Semyanov and Kullmann 2000;Matsui and Kita 2003;Drew and Vaughan 2004;Kogo et al. 2004;Cuomo et al. 2009). However, in our experiments, APs and fast glutamatergic synaptic transmission were not blocked, thus such conclusions could not be drawn, and the unexpected increase of sIPSC frequency in DBCs is likely the result of a complex network effect, by group III mGluRs acting at both GABAergic and glutamatergic synapses and multiple levels of synaptic connections, resulting in the disinhibition of a GABAergic synaptic input specific to DBCs. ...
Diverse neocortical GABAergic neurons specialize in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in 2 distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBCs) had columnar "horsetail" axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and nonpyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%), and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline) but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialized, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.
... We have also tested if synaptic inputs to the two distinct cell types differed in their regulation by glutamate receptors. We chose to study group III metabotropic glutamate receptors (mGluRs), because of previous indications from studies on rodents that group III mGluRs are differentially expressed in cortical GABAergic neurons (Dalezios et al., 2002;Somogyi et al., 2003) and selectively regulate GABAergic synaptic transmission (Semyanov & Kullmann, 2000;Kogo et al., 2004;Klar et al., 2015), and because of the large investment into developing drugs acting on group III mGluRs for the treatment of neurological and psychiatric conditions (Maksymetz et al., 2017;Charvin, 2018;Ferraguti, 2018). The results presented here, some of which have been published in abstract form (Lukacs et al., , 2020, reveal a high degree of multidimensional specialisation of human GABAergic interneurons. ...
... ;https://doi.org/10.1101https://doi.org/10. /2022 expression of group III mGluRs in the rodent cortex (Shigemoto et al., 1996;Dalezios et al., 2002;Somogyi et al., 2003;Ferraguti et al., 2005) is thought to result in the differential inhibition of GABAergic synaptic transmission to different types of interneuron and pyramidal cells (Semyanov & Kullmann, 2000;Kogo et al., 2004). However, neither the subcellular localisation nor the functions of group III mGluRs are known in the human neocortex. ...
... The copyright holder for this preprint this version posted March 5, 2022. neurotransmitter release at the level of axon terminals, in accordance with previous studies in rodents (Gerber et al., 2000;Semyanov & Kullmann, 2000;Matsui & Kita, 2003;Drew & Vaughan, 2004;Kogo et al., 2004;Cuomo et al., 2009). However, in our experiments action potentials and fast glutamatergic synaptic transmission were not blocked, thus such conclusions could not be drawn, and the unexpected increase of sIPSC frequency in DBCs is likely the result of a complex network effect, by group III mGluRs acting at both GABAergic and glutamatergic synapses and multiple levels of synaptic connections, resulting in the disinhibition of a GABAergic synaptic input specific to DBCs. ...
Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar 'horsetail' axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline), but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialized, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.
... In hippocampal circuitry, enhanced glutamate spillover has been associated with co-operative action of dendritic NMDARs, such as receptor 'priming' (Arnth- Jensen et al., 2002;Hires et al., 2008). It has been found to underlie functional intersynaptic crosstalk (Arnth- Jensen et al., 2002;Lozovaya et al., 1999;Scimemi et al., 2004), also contributing significantly to heterosynaptic plasticity (Vogt & Nicoll, 1999), and activation of metabotropic glutamate receptors outside the synaptic cleft (Min et al., 1998;Semyanov & Kullmann, 2000). ...
Glutamatergic transmission prompts K+ efflux through postsynaptic NMDA receptors. The ensuing hotspot of extracellular K+ elevation depolarizes presynaptic terminal, boosting glutamate release, but whether this also affects glutamate uptake in local astroglia has remained an intriguing question. Here, we find that the pharmacological blockade, or conditional knockout, of postsynaptic NMDA receptors suppresses use-dependent increase in the amplitude and duration of the astrocytic glutamate transporter current (IGluT), whereas blocking astrocytic K+ channels prevents the duration increase only. Glutamate spot-uncaging reveals that astrocyte depolarization, rather than extracellular K+ rises per se, is required to reduce the amplitude and duration of IGluT. Biophysical simulations confirm that local transient elevations of extracellular K+ can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K+ efflux to enhanced extrasynaptic glutamate signaling. Thus, repetitive glutamatergic transmission triggers a feedback loop in which postsynaptic K+ efflux can transiently facilitate presynaptic release while reducing local glutamate uptake.
... It is known from anatomical and pharmacological studies that metabotropic Glu receptors (mGLUR) 3, 4, 7, and 8 are expressed at the GABAergic terminals in the hippocampus [120]. However, according to Fasano et al. [64], only the presynaptically expressed mGLUR4 may provide inhibitory feedback, putatively activated by Glu released from VGLUT3+ vesicles, and thus, decrease GABAergic output. ...
Glutamate is the most abundant excitatory amino acid in the central nervous system. Neurons using glutamate as a neurotransmitter can be characterised by vesicular glutamate transporters (VGLUTs). Among the three subtypes, VGLUT3 is unique, co-localising with other “classical” neurotransmitters, such as the inhibitory GABA. Glutamate, manipulated by VGLUT3, can modulate the packaging as well as the release of other neurotransmitters and serve as a retrograde signal through its release from the somata and dendrites. Its contribution to sensory processes (including seeing, hearing, and mechanosensation) is well characterised. However, its involvement in learning and memory can only be assumed based on its prominent hippocampal presence. Although VGLUT3-expressing neurons are detectable in the hippocampus, most of the hippocampal VGLUT3 positivity can be found on nerve terminals, presumably coming from the median raphe. This hippocampal glutamatergic network plays a pivotal role in several important processes (e.g., learning and memory, emotions, epilepsy, cardiovascular regulation). Indirect information from anatomical studies and KO mice strains suggests the contribution of local VGLUT3-positive hippocampal neurons as well as afferentations in these events. However, further studies making use of more specific tools (e.g., Cre-mice, opto- and chemogenetics) are needed to confirm these assumptions.
... In hippocampal circuitry, enhanced glutamate spillover has been associated with co-operative action of dendritic NMDARs, such as receptor 'priming' (Arnth- Jensen et al., 2002;Hires et al., 2008). It has been found to underlie functional inter-synaptic crosstalk (Arnth-Jensen et al., 2002;Lozovaya et al., 1999;Scimemi et al., 2004), also contributing significantly to heterosynaptic plasticity (Vogt and Nicoll, 1999), and activation of metabotropic glutamate receptors outside the synaptic cleft (Min et al., 1998;Semyanov and Kullmann, 2000). ...
Glutamatergic transmission prompts K ⁺ efflux through postsynaptic NMDA receptors. K ⁺ depolarizes local presynaptic terminals, boosting glutamate release, but whether it also affecting glutamate uptake remains unknown. Here, we find that the pharmacological blockade, or conditional knockout, of NMDA receptors suppresses the progressive use-dependent increase in the amplitude and decay time of the astrocytic glutamate transporter current (I GluT ), whereas blocking the astrocytic inward-rectifying K ⁺ channels prevents the decay time increase only. Glutamate spot-uncaging reveals that local astrocyte depolarization, rather than extracellular K ⁺ rises on their own, reduces the amplitude and prolong the decay of I GluT . Biophysical simulations confirm that local transient elevations of extracellular K ⁺ can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K ⁺ efflux to enhanced extrasynaptic glutamate signaling. Thus, postsynaptic K ⁺ efflux facilitates presynaptic release while reducing local glutamate uptake.
