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1.
Cell Rep ; 43(7): 114382, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38905101

ABSTRACT

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity.

2.
Cell Rep ; 42(8): 112826, 2023 08 29.
Article in English | MEDLINE | ID: mdl-37471228

ABSTRACT

Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, is believed to underlie memory formation. Hebbian, postsynaptically expressed LTP requires TARPγ-8 phosphorylation for synaptic insertion of AMPA receptors (AMPARs). However, it is unknown whether TARP-mediated AMPAR insertion alone is sufficient to modify behavior. Here, we report the development of a chemogenetic tool, ExSYTE (Excitatory SYnaptic Transmission modulator by Engineered TARPγ-8), to mimic the cytoplasmic interaction of TARP with the plasma membrane in a doxycycline-dependent manner. We use this tool to examine the specific role of synaptic AMPAR potentiation in amygdala neurons that are activated by fear conditioning. Selective expression of active ExSYTE in these neurons potentiates AMPAR-mediated synaptic transmission in a doxycycline-dependent manner, occludes synaptically induced LTP, and mimics freezing triggered by cued fear conditioning. Thus, chemogenetic controlling of the TARP-membrane interaction is sufficient for LTP-like synaptic AMPAR insertion, which mimics fear conditioning.


Subject(s)
Doxycycline , Long-Term Potentiation , Long-Term Potentiation/physiology , Doxycycline/pharmacology , Synapses/metabolism , Synaptic Transmission , Lipids
3.
Nat Commun ; 14(1): 2303, 2023 04 21.
Article in English | MEDLINE | ID: mdl-37085487

ABSTRACT

The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.


Subject(s)
Cannabinoids , Mice , Animals , Cannabinoids/pharmacology , Cannabinoids/metabolism , Proteomics , Hippocampus/metabolism , Synaptic Transmission , Synapses/metabolism , Receptors, Cannabinoid/metabolism , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB1/metabolism
5.
Elife ; 102021 10 18.
Article in English | MEDLINE | ID: mdl-34658339

ABSTRACT

Ionotropic neurotransmitter receptors at postsynapses mediate fast synaptic transmission upon binding of the neurotransmitter. Post- and trans-synaptic mechanisms through cytosolic, membrane, and secreted proteins have been proposed to localize neurotransmitter receptors at postsynapses. However, it remains unknown which mechanism is crucial to maintain neurotransmitter receptors at postsynapses. In this study, we ablated excitatory or inhibitory neurons in adult mouse brains in a cell-autonomous manner. Unexpectedly, we found that excitatory AMPA receptors remain at the postsynaptic density upon ablation of excitatory presynaptic terminals. In contrast, inhibitory GABAA receptors required inhibitory presynaptic terminals for their postsynaptic localization. Consistent with this finding, ectopic expression at excitatory presynapses of neurexin-3 alpha, a putative trans-synaptic interactor with the native GABAA receptor complex, could recruit GABAA receptors to contacted postsynaptic sites. These results establish distinct mechanisms for the maintenance of excitatory and inhibitory postsynaptic receptors in the mature mammalian brain.


Subject(s)
Receptors, AMPA/metabolism , Receptors, GABA-A/metabolism , Synapses/physiology , Synaptic Transmission/physiology , Animals , Mice , Mice, Transgenic , Post-Synaptic Density/metabolism , Presynaptic Terminals/metabolism
6.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Article in English | MEDLINE | ID: mdl-33468648

ABSTRACT

Recurrent excitatory neural networks are unstable. In the hippocampus, excitatory mossy cells (MCs) receive strong excitatory inputs from dentate granule cells (GCs) and project back onto the proximal dendrites of GCs. By targeting the ipsi- and contralateral dentate gyrus (DG) along the dorsoventral axis of the hippocampus, MCs form an extensive recurrent excitatory circuit (GC-MC-GC) whose dysregulation can promote epilepsy. We recently reported that a physiologically relevant pattern of MC activity induces a robust form of presynaptic long-term potentiation (LTP) of MC-GC transmission which enhances GC output. Left unchecked, this LTP may interfere with DG-dependent learning, like pattern separation-which relies on sparse GC firing-and may even facilitate epileptic activity. Intriguingly, MC axons display uniquely high expression levels of type-1 cannabinoid receptors (CB1Rs), but their role at MC-GC synapses is poorly understood. Using rodent hippocampal slices, we report that constitutively active CB1Rs, presumably via ßγ subunits, selectively inhibited MC inputs onto GCs but not MC inputs onto inhibitory interneurons or CB1R-sensitive inhibitory inputs onto GCs. Tonic CB1R activity also inhibited LTP and GC output. Furthermore, brief endocannabinoid release from GCs dampened MC-GC LTP in two mechanistically distinct ways: during induction via ßγ signaling and before induction via αi/o signaling in a form of presynaptic metaplasticity. Lastly, a single in vivo exposure to exogenous cannabinoids was sufficient to induce this presynaptic metaplasticity. By dampening excitatory transmission and plasticity, tonic and phasic CB1R activity at MC axon terminals may preserve the sparse nature of the DG and protect against runaway excitation.


Subject(s)
Dentate Gyrus/metabolism , Excitatory Postsynaptic Potentials/physiology , Hippocampus/metabolism , Long-Term Potentiation/physiology , Receptor, Cannabinoid, CB1/genetics , Action Potentials/drug effects , Action Potentials/physiology , Animals , Animals, Newborn , Cannabinoid Receptor Agonists/pharmacology , Cannabinoid Receptor Antagonists/pharmacology , Cannabinoids/pharmacology , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Excitatory Postsynaptic Potentials/drug effects , Gene Expression , Hippocampus/cytology , Hippocampus/drug effects , Interneurons/cytology , Interneurons/drug effects , Interneurons/metabolism , Long-Term Potentiation/drug effects , Mice , Piperidines/pharmacology , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Synapses/drug effects , Synapses/physiology , Synaptic Transmission
7.
EMBO Mol Med ; 12(5): e10605, 2020 05 08.
Article in English | MEDLINE | ID: mdl-32329240

ABSTRACT

Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5-HT6 receptor-operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9-tetrahydrocannabinol (THC) to mice during adolescence induces a long-lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long-term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5-HT6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5-HT6 receptor-operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5-HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers.


Subject(s)
Marijuana Abuse , Animals , Dronabinol , Mice , Prefrontal Cortex , Receptors, Serotonin
8.
Cereb Cortex ; 29(4): 1659-1669, 2019 04 01.
Article in English | MEDLINE | ID: mdl-29917056

ABSTRACT

The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized. Here, we show that a 20-min exposure of mouse PFC slices to serotonin or the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a long-lasting depression of evoked AMPA excitatory postsynaptic currents in layer V pyramidal neurons. DOI-elicited long-term depression (LTD) of synaptic transmission is absent in slices from 5-HT2A receptor-deficient mice, is rescued by viral expression of 5-HT2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT2A receptor activation promotes phosphorylation of GluA2 AMPA receptor subunit at Ser880 and AMPA receptor internalization, indicating common mechanisms with electrically induced LTD. These findings provide one of the first examples of LTD gating under the control of a G protein-coupled receptor that might lead to imbalanced synaptic plasticity and memory impairment following a nonphysiological elevation of extracellular serotonin.


Subject(s)
Long-Term Synaptic Depression/physiology , Neuronal Plasticity/physiology , Prefrontal Cortex/physiology , Pyramidal Cells/physiology , Receptor, Serotonin, 5-HT2A/physiology , Synapses/physiology , Amphetamines/administration & dosage , Animals , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Long-Term Synaptic Depression/drug effects , Mice, Knockout , Neuronal Plasticity/drug effects , Prefrontal Cortex/drug effects , Pyramidal Cells/drug effects , Receptor, Serotonin, 5-HT2A/genetics , Receptors, AMPA/metabolism , Serotonin Receptor Agonists/administration & dosage , Synapses/drug effects
9.
ACS Chem Neurosci ; 8(5): 897-899, 2017 05 17.
Article in English | MEDLINE | ID: mdl-28459524

ABSTRACT

The serotonin 2A (5-HT2A) receptor subtype continues to attract attention as a target for numerous psychoactive drugs including psychedelic hallucinogens, antidepressants, anxiolytics, and atypical antipsychotics. 5-HT2A receptors are a principal G protein-coupled receptor subtype mediating the excitatory effects of serotonin. Nonetheless, pre- vs postsynaptic localization of 5HT2A receptors, relative to glutamatergic synapses, has remained controversial. Here, we discuss recent findings highlighting the existence and roles of presynaptic 5-HT2A receptors in regulating glutamatergic transmission and cognition.


Subject(s)
Neurons/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin/metabolism , Synapses/metabolism , Synaptic Transmission/physiology , Animals , Glutamic Acid/metabolism
10.
Proc Natl Acad Sci U S A ; 113(10): E1382-91, 2016 Mar 08.
Article in English | MEDLINE | ID: mdl-26903620

ABSTRACT

Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.


Subject(s)
Association Learning/physiology , Cerebral Cortex/physiology , Neuronal Plasticity/physiology , Receptor, Serotonin, 5-HT2A/physiology , Thalamus/physiology , Animals , Blotting, Western , Cerebral Cortex/metabolism , Electrophysiological Phenomena , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Neuronal Plasticity/genetics , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiology , Protein Kinase C/metabolism , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/genetics , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/physiology , Synapses/metabolism , Synapses/physiology , Synaptic Transmission/genetics , Synaptic Transmission/physiology , Thalamus/metabolism , Type C Phospholipases/metabolism
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