RESUMEN
BACKGROUND: There is extensive evidence implicating the metabotropic glutamate 5 (mGlu5) receptor in aspects of addiction-related behaviours. METHODS: Here, we used a well-characterized line of mGlu5-deficient mice to further examine the role of this receptor in cocaine-driven behaviours. We confirmed the previously reported deficit in hippocampal long-term potentiation and associated spatial learning impairment. RESULTS: Despite a spatial learning deficit, mGlu5-deficient mice developed and maintained a conditioned place preference to cocaine, suggesting cocaine reward and Pavlovian conditioning are intact in these animals. Notably, however, mGlu5-deficient mice exhibited a marked deficit in the extinction of a cocaine-conditioned place preference compared to wild type littermates. Moreover, in a fixed ratio operant intravenous self-administration paradigm, both genotypes showed similar responding for cocaine over two different doses, while mGlu5-deficient mice displayed enhanced responding on a progressive ratio schedule. In addition, cue-induced drug-seeking after abstinence was exaggerated in mGlu5-deficient mice. CONCLUSION: Collectively, these findings suggest that while the mGlu5 receptor may be involved in mediating the rewarding effects of cocaine, it appears necessary for the extinction of cocaine-driven behaviours.
Asunto(s)
Conducta Adictiva/genética , Conducta Adictiva/psicología , Cocaína/administración & dosificación , Extinción Psicológica/fisiología , Receptor del Glutamato Metabotropico 5/fisiología , Animales , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , AutoadministraciónRESUMEN
Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process termed 'metaplasticity', which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intracellular versus intercellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.
Asunto(s)
Comunicación Celular/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Modelos Neurológicos , Plasticidad Neuronal/fisiología , Transducción de Señal/fisiología , Sinapsis/metabolismo , Adenosina Trifosfato/metabolismo , Región CA1 Hipocampal/fisiología , HidrólisisRESUMEN
Long-term potentiation (LTP) in the hippocampus is a fundamental process underlying learning and memory in the brain. At CA3-CA1 synapses, three discrete forms of LTP (LTP1, 2, and 3) have been differentiated on the basis of their persistence, maintenance mechanisms, Ca(2+) signaling pathways, expression loci, and electrophysiological requirements. We previously showed that LTP2 and LTP3 involve a presynaptic expression component that is established in a translation-dependent manner. Here we investigate the locus of translation required for presynaptic expression. Neurotransmitter release rate was estimated via FM 1-43 destaining from CA3 terminals in hippocampal slices from male Wistar rats (6-8 weeks). Destaining was measured at sites making putative contact with CA1 dendritic processes in stratum radiatum that had been filled with a membrane impermeable translation inhibitor and a fluorescent indicator. Our results suggest that inhibition of postsynaptic translation eliminates the enhanced release ordinarily observed at 160 min post-LTP induction, and that this effect is limited to sites closely apposed to the filled postsynaptic cell. We conclude that postsynaptic translation is required for the presynaptic component of LTP2 and LTP3 expression. These data considerably strengthen the mechanistic separation of LTP1, 2, and 3 and provide evidence for an expanded repertoire of communication between synaptic elements.
RESUMEN
Long-term potentiation (LTP) is an important process underlying learning and memory in the brain. At CA3-CA1 synapses in the hippocampus, three discrete forms of LTP (LTP1, 2, and 3) can be differentiated on the basis of maintenance and induction mechanisms. However, the relative roles of pre- and post-synaptic expression mechanisms in LTP1, 2, and 3 are unknown. Neurotransmitter release in the expression of LTP1, 2, and 3 was measured via FM 1-43 destaining from CA3 terminals in hippocampal slices from male Wistar rats (7-8 wk). No difference in vesicle turnover rate was observed for LTP1 up to 160 min following induction by one train of theta-burst stimulation (1TBS). A presynaptic enhancement was found for LTP2 at 160 min after induction by 4TBS, and for LTP3 at both 80 and 160 min after induction by 8TBS. Inhibition of nitric oxide (NO) signaling blocked both LTP2 and LTP3 maintenance and the associated enhanced release. LTP2 maintenance and its presynaptic expression were dependent on protein synthesis, but not gene transcription. LTP3 maintenance was dependent on both translation and transcription, but like LTP2, the enhanced release only required translation. These data considerably strengthen the mechanistic separation of LTP1, 2, and 3, supporting a model of multiple, discrete forms of LTP at CA3-CA1 synapses rather than different temporal phases.
Asunto(s)
Potenciación a Largo Plazo/fisiología , Proteínas del Tejido Nervioso/biosíntesis , Óxido Nítrico/fisiología , Terminales Presinápticos/fisiología , Animales , Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Óxidos N-Cíclicos/farmacología , Estimulación Eléctrica , Fenómenos Electrofisiológicos , Inhibidores Enzimáticos/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Depuradores de Radicales Libres/farmacología , Hipocampo/fisiología , Imidazoles/farmacología , Técnicas In Vitro , Cinética , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Microscopía Fluorescente , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Terminales Presinápticos/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Transmisión SinápticaRESUMEN
The role of postsynaptic action potentials (APs) in the induction of long-term potentiation (LTP) remains unclear, but has important implications for theories of associative learning in the brain. In area CA1 of hippocampus, at least three discrete forms of LTP coexist, each displaying unique decay kinetics and involving different signalling and effector systems. The present work investigates whether these forms of LTP also differ in their requirement for postsynaptic APs. Inhibition of APs during theta-burst stimulation (TBS) had no effect on the persistence of short-lasting LTP (LTP 1), but reduced the persistence of more durable forms (LTP 2 and 3). Calcium imaging revealed different requirements for APs in generating calcium signals in spines, dendrites, and somata, consistent with their known roles in the induction of each form of LTP. Finally, short-lasting LTP was endowed with dramatically enhanced persistence by the presentation of TBS-patterned APs alone. These data reveal that the requirement for APs in LTP induction is dependent on the form of LTP under investigation, supporting the contention that different neuronal learning mechanisms coexist in hippocampal area CA1.
Asunto(s)
Potenciales de Acción/fisiología , Potenciación a Largo Plazo/fisiología , Células Piramidales/fisiología , Animales , Señalización del Calcio/fisiología , Estimulación Eléctrica , Electrofisiología , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas WistarRESUMEN
Long-term potentiation (LTP) of synaptic transmission is a primary experimental model of memory formation in neuronal circuits. Because of the intellectual appeal and scientific fecundity of the field, it is perhaps unsurprising that the literature on LTP contains many complex and often contradictory findings. Recognition that LTP is not a unitary phenomenon and mechanisms can differ between brain regions has resolved some controversy. However, further categorization can be made of mechanistically discrete forms of LTP at the same set of synapses. LTP1, LTP2 and LTP3 have previously been defined according to differences in the longevity and general molecular mechanisms of LTP. This review aims to reinvigorate and extend this concept as a useful framework to disentangle the mechanisms of LTP.
Asunto(s)
Encéfalo/citología , Potenciación a Largo Plazo/fisiología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Animales , Modelos BiológicosRESUMEN
Calcium regulates numerous processes in the brain. How one signal can coordinate so many diverse actions, even within the same neurone, is the subject of intense investigation. Here we have used two-photon calcium imaging to determine the mechanism that enables calcium to selectively and appropriately induce different forms of long-term potentiation (LTP) in rat hippocampus. Short-lasting LTP (LTP 1) required activation of ryanodine receptors (RyRs), which selectively increased calcium in synaptic spines. LTP of intermediate duration (LTP 2) was dependent on activation of inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and subsequent calcium release specifically in dendrites. Long-lasting LTP (LTP 3) was selectively dependent on L-type voltage-dependent calcium channels (L-VDCCs), which generated somatic calcium influx. Activation of NMDA receptors was necessary, but not sufficient, for the generation of appropriate calcium signals in spines and dendrites, and the induction of LTP 1 and LTP 2. These results suggest that the selective induction of different forms of LTP is achieved via spatial segregation of functionally distinct calcium signals.
Asunto(s)
Señalización del Calcio , Hipocampo/metabolismo , Potenciación a Largo Plazo , Neuronas/metabolismo , Animales , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/metabolismo , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Receptores de Inositol 1,4,5-Trifosfato , Cinética , Potenciación a Largo Plazo/efectos de los fármacos , Compuestos Macrocíclicos , Masculino , Neuronas/efectos de los fármacos , Nifedipino/farmacología , Oxazoles/farmacología , Ratas , Ratas Wistar , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Rojo de Rutenio/farmacología , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
Maintaining synaptic transmission requires replenishment of docked synaptic vesicles within the readily releasable pool (RRP) from synaptic vesicle clusters in the synapsin-bound reserve pool. We show that synapsin forms a complex with phosphatidylinositol 3-kinase (PI 3-kinase) in intact nerve terminals and that synapsin-associated kinase activity increases on depolarization. Disruption of either PI 3-kinase activity or its interaction with synapsin inhibited replenishment of the RRP, but did not affect exocytosis from the RRP. Thus we conclude that a synapsin-associated PI 3-kinase activity plays a role in synaptic vesicle delivery to the RRP. This also suggests that PI 3-kinase contributes to the maintenance of synaptic transmission during periods of high activity, indicating a possible role in synaptic plasticity.
Asunto(s)
Fosfatidilinositol 3-Quinasas/metabolismo , Sinapsinas/metabolismo , Vesículas Sinápticas/fisiología , Androstadienos/farmacología , Animales , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Exocitosis , Ácido Glutámico/metabolismo , Morfolinas/farmacología , Terminaciones Nerviosas/metabolismo , Plasticidad Neuronal , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ratas , Transmisión Sináptica/fisiología , WortmaninaRESUMEN
Accumulation of amyloid-beta peptide (Abeta) is widely believed to play a critical role in the pathogenesis of Alzheimer's disease. Although amyloid-containing plaques are a key neuropathological feature of AD, soluble forms of Abeta can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for much of the memory deficit seen early in the disease. Here, we investigate the mechanism underlying the effects of Abeta on long-term potentiation (LTP) in area CA1 of rat hippocampus. Extracellular field recordings were made in area CA1 of hippocampal slices taken from young, adult male rats. A non-toxic concentration of Abeta (200 nM) produced a rapid inhibition of LTP induced by 100 Hz stimulation while having no long-term effect on normal synaptic transmission. The same dose of Abeta had no effect on long-term depression (LTD) induced by 1200 pulses at 1 or 3 Hz. Picrotoxin had no effect on the inhibition of LTP, suggesting Abeta does not act by enhancing GABAergic transmission. Since the LTP induction in this study was dependent on N-methyl-D-aspartate (NMDA) receptor activation, we looked at the effect of Abeta on isolated NMDA receptor-mediated field potentials. Abeta produced a small but significant inhibition of NMDA receptor-mediated synaptic potentials ( approximately 25%). However, a low dose of MK-801 (0.5 microM) that produced a similar inhibition of NMDA potentials had no effect on LTP induction but completely blocked LTD induction. These results suggest that Abeta does not inhibit LTP via effects on NMDA receptors, but rather interferes with a downstream pathway.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Hipocampo/anatomía & histología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Picrotoxina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The essential role of calcium in the induction of long-term potentiation (LTP) has been well established. In particular, calcium influx via the N-methyl-D-aspartate (NMDA) receptor (NMDAR) is important for LTP induction in many pathways. However, the specific roles of other calcium sources in hippocampal LTP are less clear. The aim of the present study was to determine the appropriate conditions and extent to which non-NMDAR Ca(2+) sources contribute to the induction of different forms of LTP in area CA1 of hippocampal slices. Increasing numbers of theta-burst trains (1, 4, and 8 TBS) induced LTP of increasing magnitude and persistence. Inhibition of ryanodine receptors caused inhibition of weak LTP induced by 1 TBS, but had no effect on more robust forms of LTP. Inhibition of IP3 receptors inhibited moderate LTP induced by 4 TBS, but had no effect when 1 TBS or 8 TBS were used. Inhibition of L-type voltage-dependent Ca(2+) channels inhibited strong LTP induced by 8 TBS, but had no effect on weaker forms of LTP. These results show that different Ca(2+) sources have different thresholds for activation by TBS trains. Furthermore, each Ca(2+) source appears to be tuned to the induction of a different form of LTP. Such tuning could reflect an important link between different LTP induction and maintenance mechanisms.