RESUMO
Neuromedin B (NMB) and gastrin-releasing peptide (GRP) are the two mammalian analogs in the bombesin peptide family that exert a variety of actions including emotional processing, appetitive behaviors, cognition, and tumor growth. The bombesin-like peptides interact with three receptors: the NMB-preferring bombesin 1 (BB1) receptors, the GRP-preferring bombesin 2 (BB2) receptors and the orphan bombesin 3 (BB3) receptors. Whereas, injection of bombesin into the central amygdala reduces satiety and modulates blood pressure, the underlying cellular and molecular mechanisms have not been determined. As administration of bombesin induces the expression of Fos in the lateral nucleus of the central amygdala (CeL) which expresses BB1 receptors, we probed the effects of NMB on CeL neurons using in vitro and in vivo approaches. We showed that activation of the BB1 receptors increased action potential firing frequency recorded from CeL neurons via inhibition of the inwardly rectifying K+ (Kir) channels. Activities of phospholipase Cß and protein kinase C were required, whereas intracellular Ca2+ release was unnecessary for BB1 receptor-elicited potentiation of neuronal excitability. Application of NMB directly into the CeA reduced blood pressure and heart rate and significantly reduced fear-potentiated startle. We may provide a cellular and molecular mechanism whereby bombesin-like peptides modulate anxiety and fear responses in the amygdala.
Assuntos
Neurocinina B , Peptídeos , Animais , Tonsila do Cerebelo/metabolismo , Bombesina/farmacologia , Bombesina/metabolismo , Medo , Mamíferos/metabolismo , Neurônios/metabolismo , Peptídeos/metabolismo , Receptores da Bombesina/metabolismo , Neurocinina B/metabolismoRESUMO
Arginine vasopressin (AVP) serves as a neuromodulator in the brain. The hippocampus is one of the major targets for AVP, as it has been demonstrated that the hippocampus receives vasopressinergic innervation and expresses AVP receptors. The dentate gyrus (DG) granule cells (GCs) serve as a gate governing the inflow of information to the hippocampus. High densities of AVP receptors are expressed in the DG GCs. However, the roles and the underlying cellular and molecular mechanisms of AVP in the DG GCs have not been determined. We addressed this question by recording from the DG GCs in rat hippocampal slices. Our results showed that application of AVP concentration-dependently evoked an inward holding current recorded from the DG GCs. AVP depolarized the DG GCs and increased their action potential firing frequency. The excitatory effects of AVP were mediated by activation of V1a receptors and required the function of phospholipase Cß (PLCß). Whereas intracellular Ca2+ release and protein kinase C activity were unnecessary, PLCß-induced depletion of phosphatidylinositol 4,5-bisphosphate was involved in AVP-evoked excitation of the DG GCs. AVP excited the DG GCs by depression of the ATP-sensitive K+ channels, which were required for AVP-elicited facilitation of long-term potentiation at the perforant path-GC synapses. Our results may provide a cellular and molecular mechanism to explain the physiological functions of AVP, such as learning and memory, and pathologic disorders like anxiety.
Assuntos
Arginina Vasopressina , Potenciação de Longa Duração , Trifosfato de Adenosina/farmacologia , Animais , Arginina Vasopressina/farmacologia , Giro Denteado , Potenciação de Longa Duração/fisiologia , Fosfolipase C beta , RatosRESUMO
In neurons, Ca2+ is essential for a variety of physiological processes that regulate gene transcription to neuronal growth and their survival. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ions (MPP+) are potent neurotoxins that selectively destroys the dopaminergic (DA) neurons and mimics Parkinson's disease (PD) like symptoms, but the mechanism as how MPP+/MPTP effects DA neuron survival is not well-understood. In the present study, we found that MPP+ treatment increased the level of reactive oxygen species (ROS) that activates and upregulates the expression and function of melastatin-like transient receptor potential (TRPM) subfamily member, melastatin-like transient receptor potential channel 2 (TRPM2). Correspondingly, TRPM2 expression was also increased in substantia nigra of MPTP-induced PD mouse model and PD patients. ROS-mediated activation of TRPM2 resulted in an increased intracellular Ca2+, which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca2+ overload caused by MPP+-induced ROS also affected calpain activity, followed by increased caspase 3 activities and activation of downstream apoptotic pathway. On the other hand, quenching of H2O2 by antioxidants, resveratrol (RSV), or N-acetylcysteine (NAC) effectively blocked TRPM2-mediated Ca2+ influx, decreased intracellular Ca2+ overload, and increased cell survival. Importantly, pharmacological inhibition of TRPM2 or knockdown of TRPM2 using siRNA, but not control siRNA, showed an increased protection by preventing MPP+-induced Ca2+ increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP+-induced dopaminergic neuronal cell death.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Doença de Parkinson/metabolismo , Canais de Cátion TRPM/biossíntese , Idoso , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Feminino , Herbicidas/toxicidade , Humanos , Intoxicação por MPTP/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/patologia , Canais de Cátion TRPM/genéticaRESUMO
The hippocampus is a crucial component for cognitive and emotional processing. The subiculum provides much of the output for this structure but the modulation and function of this region is surprisingly under-studied. The neuromodulator somatostatin (SST) interacts with five subtypes of SST receptors (sst1 to sst5 ) and each of these SST receptor subtypes is coupled to Gi proteins resulting in inhibition of adenylyl cyclase (AC) and decreased level of intracellular cAMP. SST modulates many physiological functions including cognition, emotion, autonomic responses and locomotion. Whereas SST has been shown to depress neuronal excitability in the subiculum, the underlying cellular and molecular mechanisms have not yet been determined. Here, we show that SST hyperpolarized two classes of subicular neurons with a calculated EC50 of 0.1 µM. Application of SST (1 µM) induced outward holding currents by primarily activating K+ channels including the G-protein-activated inwardly-rectifying potassium channels (GIRK) and KCNQ (M) channels, although inhibition of cation channels in some cells may also be implicated. SST-elicited hyperpolarization was mediated by activation of sst2 receptors and required the function of G proteins. The SST-induced hyperpolarization resulted from decreased activity of AC and reduced levels of cAMP but did not require the activity of either PKA or PKC. Inhibition of Epac2, a guanine nucleotide exchange factor, partially blocked SST-mediated hyperpolarization of subicular neurons. Furthermore, application of SST resulted in a robust depression of subicular action potential firing and the SST-induced hyperpolarization was responsible for its inhibitory action on LTP at the CA1-subicilum synapses. Our results provide a novel cellular and molecular mechanism that may explain the roles of SST in modulation of subicular function and be relevant to SST-related physiological functions.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hipocampo/citologia , Canais de Potássio KCNQ/metabolismo , Neurônios/efeitos dos fármacos , Somatostatina/farmacologia , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , AMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Fatores de Troca do Nucleotídeo Guanina/agonistas , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Modelos Biológicos , Rede Nervosa/efeitos dos fármacos , Neurônios/classificação , Neurotransmissores/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/farmacologia , Somatostatina/agonistas , Somatostatina/antagonistas & inibidores , Tetrodotoxina/farmacologiaRESUMO
Whereas corticotropin-releasing factor (CRF) has been considered as the most potent epileptogenic neuropeptide in the brain, its action site and underlying mechanisms in epilepsy have not been determined. Here, we found that the entorhinal cortex (EC) expresses high level of CRF and CRF2 receptors without expression of CRF1 receptors. Bath application of CRF concentration-dependently increased the frequency of picrotoxin (PTX)-induced epileptiform activity recorded from layer III of the EC in entorhinal slices although CRF alone did not elicit epileptiform activity. CRF facilitated the induction of epileptiform activity in the presence of subthreshold concentration of PTX which normally would not elicit epileptiform activity. Bath application of the inhibitor for CRF-binding proteins, CRF6-33, also increased the frequency of PTX-induced epileptiform activity suggesting that endogenously released CRF is involved in epileptogenesis. CRF-induced facilitation of epileptiform activity was mediated via CRF2 receptors because pharmacological antagonism and knockout of CRF2 receptors blocked the facilitatory effects of CRF on epileptiform activity. Application of the adenylyl cyclase (AC) inhibitors blocked CRF-induced facilitation of epileptiform activity and elevation of intracellular cyclic AMP (cAMP) level by application of the AC activators or phosphodiesterase inhibitor increased the frequency of PTX-induced epileptiform activity, demonstrating that CRF-induced increases in epileptiform activity are mediated by an increase in intracellular cAMP. However, application of selective protein kinase A (PKA) inhibitors reduced, not completely blocked CRF-induced enhancement of epileptiform activity suggesting that PKA is only partially required. Our results provide a novel cellular and molecular mechanism whereby CRF modulates epilepsy.
Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Córtex Entorrinal/metabolismo , Córtex Entorrinal/fisiologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , AMP Cíclico/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologiaRESUMO
Adenosine is an inhibitory neuromodulator that exerts antiepileptic effects in the brain and the entorhinal cortex (EC) is an essential structure involved in temporal lobe epilepsy. Whereas microinjection of adenosine into the EC has been shown to exert powerful antiepileptic effects, the underlying cellular and molecular mechanisms in the EC have not been determined yet. We tested the hypothesis that adenosine-mediated modulation of synaptic transmission contributes to its antiepileptic effects in the EC. Our results demonstrate that adenosine reversibly inhibited glutamatergic transmission via activation of adenosine A1 receptors without effects on GABAergic transmission in layer III pyramidal neurons in the EC. Adenosine-induced depression of glutamatergic transmission was mediated by inhibiting presynaptic glutamate release probability and decreasing the number of readily releasable vesicles. Bath application of adenosine also reduced the frequency of the miniature EPSCs recorded in the presence of TTX suggesting that adenosine may interact with the exocytosis processes downstream of Ca(2+) influx. Both Gαi/o proteins and the protein kinase A pathway were required for adenosine-induced depression of glutamatergic transmission. We further showed that bath application of picrotoxin to the EC slices induced stable epileptiform activity and bath application of adenosine dose-dependently inhibited the epileptiform activity in this seizure model. Adenosine-mediated depression of epileptiform activity was mediated by activation of adenosine A1 receptors and required the functions of Gαi/o proteins and protein kinase A pathway. Our results suggest that the depression of glutamatergic transmission induced by adenosine contributes to its antiepileptic effects in the EC.
Assuntos
Adenosina/metabolismo , Córtex Entorrinal/metabolismo , Ácido Glutâmico/metabolismo , Animais , Técnicas In Vitro , Ratos , Ratos Sprague-Dawley , Convulsões/metabolismoRESUMO
Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters Ca²âº homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca²âº entry (SOCE), which is critical for maintaining ER Ca²âº levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and Ca²âº entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca²âº levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca²âº entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1â»/â» mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating Ca²âº homeostasis and inhibiting the UPR and thus contributes to neuronal survival.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Sinalização do Cálcio/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/fisiologia , Canais de Cátion TRPC/biossíntese , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Química Encefálica , Canais de Cálcio , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Neurônios Dopaminérgicos/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Camundongos , Proteínas do Tecido Nervoso/fisiologia , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Molécula 1 de Interação Estromal , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/fisiologiaRESUMO
Though loss of function in CBP/p300, a family of CREB-binding proteins, has been causally associated with a variety of human neurological disorders, such as Rubinstein-Taybi syndrome, Huntington's disease and drug addiction, the role of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, in modulating neurological functions remains completely unknown. Through the examination of EID1 expression and cellular distribution, we discovered that there is a significant increase of EID1 nuclear translocation in the cortical neurons of Alzheimer's disease (AD) patient brains compared to that of control brains. To study the potential effects of EID1 on neurological functions associated with learning and memory, we generated a transgenic mouse model with a neuron-specific expression of human EID1 gene in the brain. Overexpression of EID1 led to an increase in its nuclear localization in neurons mimicking that seen in human AD brains. The transgenic mice had a disrupted neurofilament organization and increase of astrogliosis in the cortex and hippocampus. Furthermore, we demonstrated that overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function in the transgenic mice. Our results indicated that the negative effects of extra nuclear EID1 in transgenic mouse brains are likely due to its inhibitory function on CBP/p300 mediated histone and p53 acetylation, thus affecting the expression of downstream genes involved in the maintenance of neuronal structure and function. Together, our data raise the possibility that alteration of EID1 expression, particularly the increase of EID1 nuclear localization that inhibits CBP/p300 activity in neuronal cells, may play an important role in AD pathogenesis.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Transtornos da Memória/etiologia , Plasticidade Neuronal/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Animais , Encéfalo/anatomia & histologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Núcleo Celular/patologia , Estimulação Elétrica , Proteína Glial Fibrilar Ácida/metabolismo , Histonas/metabolismo , Humanos , Técnicas In Vitro , Aprendizagem em Labirinto/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/patologia , Proteínas Nucleares/genética , Técnicas de Patch-Clamp , Fosfoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Transporte Proteico/fisiologia , Proteínas Repressoras/genética , Teratocarcinoma/patologia , Transfecção , Proteína Supressora de Tumor p53/metabolismo , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
The entorhinal cortex (EC) is regarded as the gateway to the hippocampus and thus is essential for learning and memory. Whereas the EC expresses a high density of GABA(B) receptors, the functions of these receptors in this region remain unexplored. Here, we examined the effects of GABA(B) receptor activation on neuronal excitability in the EC and spatial learning. Application of baclofen, a specific GABA(B) receptor agonist, inhibited significantly neuronal excitability in the EC. GABA(B) receptor-mediated inhibition in the EC was mediated via activating TREK-2, a type of two-pore domain K(+) channels, and required the functions of inhibitory G proteins and protein kinase A pathway. Depression of neuronal excitability in the EC underlies GABA(B) receptor-mediated inhibition of spatial learning as assessed by Morris water maze. Our study indicates that GABA(B) receptors exert a tight control over spatial learning by modulating neuronal excitability in the EC.
Assuntos
Córtex Entorrinal/metabolismo , Inibição Neural/fisiologia , Neurônios/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Receptores de GABA-B/metabolismo , Comportamento Espacial/fisiologia , Proteínas de Ancoragem à Quinase A/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Baclofeno/farmacologia , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Eletrofisiologia , Córtex Entorrinal/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Imuno-Histoquímica , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Comportamento Espacial/efeitos dos fármacos , Transfecção/métodosRESUMO
The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia, and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by alpha(2A) adrenergic receptors and required the functions of Galpha(i) proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated by activation of TREK-2, a type of two-pore domain K(+) channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine. Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels.
Assuntos
Potenciais de Ação , Córtex Entorrinal/citologia , Neurônios , Norepinefrina/farmacologia , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Córtex Entorrinal/fisiologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Canais de Potássio de Domínios Poros em Tandem/genética , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Transdução de Sinais/fisiologiaRESUMO
The entorhinal cortex (EC) is regarded as the gateway to the hippocampus; the superficial layers (layers I-III) of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. The superficial layers of the EC receive strong serotonergic projections from the raphe nuclei. However, the function of serotonin in the EC is still elusive. In the present study, we examined the molecular and cellular mechanisms underlying serotonin-mediated inhibition of the neuronal excitability in the superficial layers (layers II and III) of the EC. Application of serotonin inhibited the excitability of stellate and pyramidal neurons in the superficial layers of the EC by activating the TWIK-1 type of the two-pore domain K(+) channels. The effects of 5-HT were mediated via 5-HT(1A) receptors and required the function of Galpha(i3) subunit and protein kinase A. Serotonin-mediated inhibition of EC activity resulted in an inhibition of hippocampal function. Our study provides a cellular mechanism that might at least partially explain the roles of serotonin in many physiological functions and neurological diseases.
Assuntos
Córtex Entorrinal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Serotonina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Córtex Entorrinal/fisiologia , Potenciais Pós-Sinápticos Excitadores , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Proteínas do Tecido Nervoso , Neurônios/fisiologia , Canais de Potássio/fisiologia , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/fisiologia , Transdução de SinaisRESUMO
Two distinct forms of long-term depression (LTD) exist at mossy fiber synapses between dentate gyrus granule cells and hippocampal CA3 stratum lucidum interneurons. Although induction of each form of LTD requires an elevation of postsynaptic intracellular Ca2+, at Ca2+-impermeable AMPA receptor (CI-AMPAR) synapses, induction is NMDA receptor (NMDAR) dependent, whereas LTD at Ca2+-permeable AMPA receptor (CP-AMPAR) synapses is NMDAR independent. However, the expression locus of either form of LTD is not known. Using a number of criteria, including the coefficient of variation, paired-pulse ratio, AMPA-NMDA receptor activity, and the low-affinity AMPAR antagonist gamma-D-glutamyl-glycine, we demonstrate that LTD expression at CP-AMPAR synapses is presynaptic and results from reduced transmitter release, whereas LTD expression at CI-AMPAR synapses is postsynaptic. The N-ethylmaleimide-sensitive fusion protein-AP2-clathrin adaptor protein 2 inhibitory peptide pep2m occluded LTD expression at CI-AMPAR synapses but not at CP-AMPAR synapses, confirming that CI-AMPAR LTD involves postsynaptic AMPAR trafficking. Thus, mossy fiber innervation of CA3 stratum lucidum interneurons occurs via two parallel systems targeted to either Ca2+-permeable or Ca2+-impermeable AMPA receptors, each with a distinct expression locus for long-term synaptic plasticity.