RESUMEN
The medial prefrontal cortex (mPFC) is known to be critical for specific forms of long-term recognition memory, however the cellular mechanisms in the mPFC that underpin memory maintenance have not been well characterized. This study examined the importance of phosphorylation of cAMP responsive element binding protein (CREB) in the mPFC for different forms of long-term recognition memory in the rat. Adenoviral transduction of the mPFC with a dominant-negative inhibitor of CREB impaired object-in-place memory following a 6 or 24 h retention delay, but no impairment was observed following delays of 5 min or 3 h. Long-term object temporal order memory and spatial temporal order memory was also impaired. In contrast, there were no impairments in novel object recognition or object location memory. These results establish, for the first time, the importance of CREB phosphorylation within the mPFC for memory of associative and temporal information crucial to recognition.
Asunto(s)
Asociación , Proteína de Unión a CREB/fisiología , Memoria a Largo Plazo/fisiología , Corteza Prefrontal/metabolismo , Reconocimiento en Psicología/fisiología , Memoria Espacial/fisiología , Transcripción Genética/genética , Animales , Conducta Animal/fisiología , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Dependovirus , Masculino , Fosforilación/fisiología , RatasRESUMEN
Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal-PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal-PFC NMDAR-mediated synaptic transmission. We show that dopamine-dependent LTD of NMDAR-mediated transmission profoundly disrupts normal synaptic transmission between hippocampus and PFC. These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia.
Asunto(s)
Hipocampo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Corteza Prefrontal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Humanos , Receptores de Dopamina D2/fisiología , Transmisión SinápticaRESUMEN
Object-in-place associative recognition memory depends on an interaction between the hippocampus (HPC), perirhinal (PRH), and medial prefrontal (mPFC) cortices, yet the contribution of glutamate receptor neurotransmission to these interactions is unknown. NMDA receptors (NMDAR) in the HPC were critical for encoding of object-in-place memory but not for single-item object recognition. Next, a disconnection procedure was used to examine the importance of "concurrent" glutamate neurotransmission in the HPC-mPFC and HPC-PRH. Contralateral unilateral infusions of NBQX (AMPAR antagonist), into the HPC-mPFC, or HPC-PRH, either before acquisition or test, impaired object-in-place performance. Thus, both circuits are necessary for encoding and retrieval. Crossed unilateral AP5 (NMDAR antagonist) infusions into the HPC-mPFC or HPC-PRH impaired encoding, but not retrieval. Specifically crossed HPC-mPFC infusions impaired both short-term (5 min) and longer term (1 h) memory while HPC-PRH infusions impaired longer term memory only. This delay-dependent effect of AP5 in the HPC-PRH on object-in-place memory, accords with its effects in the PRH, on single item object recognition memory, thereby suggesting that a single PRH synaptic plasticity mechanism underpins different recognition memory processes. Further, blocking excitatory neurotransmission in any pair of structures within the networks impaired "both" encoding and retrieval, thus object-in-place memory clearly requires network interdependency across multiple structures.
Asunto(s)
Hipocampo/fisiología , Corteza Prefrontal/fisiología , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reconocimiento en Psicología/fisiología , Lóbulo Temporal/fisiología , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Catéteres de Permanencia , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Hipocampo/efectos de los fármacos , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Plasticidad Neuronal , Pruebas Neuropsicológicas , Corteza Prefrontal/efectos de los fármacos , Quinoxalinas/farmacología , Ratas , Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Reconocimiento en Psicología/efectos de los fármacos , Lóbulo Temporal/efectos de los fármacosRESUMEN
Recognition memory, involving the ability to discriminate between a novel and familiar object, depends on the integrity of the perirhinal cortex (PRH). Glutamate, the main excitatory neurotransmitter in the cortex, is essential for many types of memory processes. Of the subtypes of glutamate receptor, metabotropic receptors (mGluRs) have received less study than NMDA receptors; thus, the reported experiments examined the role of mGluRs in familiarity discrimination in the rat PRH. Experiments 1 and 2 assessed the effects of systemic administration of MPEP, a group I mGluR (specifically mGluR5) antagonist, and/or LY341495, a group II mGluR antagonist, on a spontaneous object novelty preference task. Simultaneous antagonism of both group I and II mGluRs impaired familiarity discrimination following a 24-h but not a 15-min delay, while antagonism of either mGluR subtype alone had no effect at either delay. The impairment was in acquisition, as in Experiment 3 coadministration of MPEP and LY341495 did not affect recognition memory performance when administered either after the sample phase or prior to test. The impairment in long-term recognition memory was mediated by mGluRs in the PRH, as localized intracortical antagonism of group I and II mGluRs also produced a deficit (Experiment 4). No evidence was found for an involvement of group III mGluRs in the acquisition of long-term familiarity discrimination (Experiment 5). These findings establish that glutamatergic neurotransmission in the PRH via group I and II mGluRs is crucial for the acquisition, but not for the consolidation or retrieval of long-term object recognition memory.