Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

Abstract

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.T he hippocampus to medial prefrontal cortex (PFC) projection is important for executive function and working and long-term memory (1, 2). Glutamatergic neurons of the ventral hippocampal cornu ammonis 1 (CA1) region project directly to layers 2-6 of ipsilateral PFC, and this connection synchronizes PFC and hippocampal activity during particular behavioral conditions (3-5). Disruption of hippocampal-PFC synchrony is associated with cognitive deficits that occur in disorders such as schizophrenia (6). Hippocampal-PFC uncoupling can be achieved by NMDA receptor (NMDAR) antagonism (7), and NMDAR hypofunction is a recognized feature of schizophrenia (8). However, it is unclear, first, how changes in NMDAR function at this synapse may arise, and second, how NMDAR hypofunction affects hippocampal-PFC synaptic transmission.Canonically, NMDARs are considered to contribute little to single synaptic events, but the slow kinetics of NMDARs contribute to maintaining depolarization, leading to the generation of bursts of action potentials (9-13). Furthermore, NMDARs coordinate spike timing relative to the phase of field potential oscillations (14, 15). NMDAR transmission itself undergoes synaptic plasticity (16,17), and this can have a profound effect on sustained depolarization, burst firing, synaptic integration, and metaplasticity (9,11,18,19). In PFC, NMDARs are oppositely regulated by dopamine receptors; D1-like receptors (D1Rs) potentiate and D2-like receptors (D2Rs) depress NMDAR currents (20). Interestingly, NMDAR hypofunction (8, 21) and dopamine D2 receptor activity (22) are potentially converging mechanisms contributing to schizophrenia (23).We now examine the contribution of NMDARs to transmission at the hippocampal-PFC synapse. We show that NMDAR activity provides sustained depolarization that can trigger action potentials during bursts of hippocampal input to PFC. We next demonstrate that dopamine D2 receptor-dependent long-term depression (LTD) of NMDAR transmission profoundly attenuates summation of synaptic transmission and neuronal firing at the hippocampal-PFC input. These findings allow for a mechanistic understanding of how alterations in dopamine and NMDAR function can lead t...

Plasticity in prefrontal cortex induced by coordinated nucleus reuniens and hippocampal synaptic transmission

“…Previous reports have shown varied effects on glutamatergic transmission in mPFC, including both potentiation and depression of AMPAR and NMDAR mediated components, mediated via D1Rs and D2Rs (Banks et al 2015, Gao et al 2001, Gonzalez-Islas & Hablitz 2003, Law-Tho et al 1994, Seamans et al 2001, Urban et al 2002. In this study neither NRe or HPC AMPA EPSPs at -70 mV were affected by either D1R or D2R agonists.…”

“…Brains were rapidly removed and placed into ice-cold sucrose solution (in mM: 189 sucrose, 26 NaHCO3, 10 D-glucose, 5 MgSO4, 3 KCl, 1.25 NaH2PO4, 0.2 CaCl2) bubbled with 95 % O2/5 % CO2. The brain was sectioned at 11° using a custom brain matrix as previously described (Banks et al 2015) and modified coronal slices were cut at 350 µm thickness using a vibratome (7000smz-2, Camden Instruments), hemisected and incubated at 34 °C for 1 hour after dissection in a slice holding chamber filled with artificial cerebrospinal fluid (aCSF,in mM: 124 NaCl,26 NaHCO3,10 Dglucose,3 KCl,2 CaCl2,1.25 NaH2PO4,1 MgSO4). Slices were subsequently stored at room temperature until use.…”

“…Slices at ~ 3.0 mm anterior to bregma were used for electrophysiology, placed in a submerged recording chamber and perfused with 34 °C aCSF at ~2ml.min -1 . A stimulating electrode (FH-Co, CBABAP50, USA) was placed on the hippocampal fibre bundle as previously described (Banks et al 2015). Pyramidal neurons in prelimbic cortex (layer 5 unless otherwise stated) were targeted under oblique infra-red illumination based on somatic morphology and patch clamped using 2-6 MΩ boroscillicate glass electrodes (GC150-10F, Harvard Apparatus) filled with potassium gluconate internal for current-clamp experiments (in mM: 120 k-gluconate, 40 HEPES, 10 KCl, 2 NaCl, 2 MgATP, 1 MgCl, 0.3 NaGTP, 0.2 EGTA, 0.1 Alexa-594 hydrazide) or cesium methylsulfonate for voltage clamp (130 CsMeSO4,10 HEPES,8 NaCl,4 MgATP,0.5 EGTA,0.3 NaGTP, hydrazide).…”

“…In this study we focussed on the NRe and HPC projections to layer 5 pyramidal neurons -one of the primary output cells of prelimbic cortex and the main target for HPC afferents (Liu & Carter 2018). Modified coronal mPFC slices were prepared as described previously (Banks et al 2015, Parent et al 2010. To activate NRe axons in PFC an LED was directed over L5 cell somata and proximal dendrites via the microscope objective ( Fig 1C).…”

Comportamento compulsivo à cocaína e as implicações no sistema colinérgico muscarínico

“…A natureza dessa conexão é essencialmente glutamatérgica e GABAérgica e sabe-se que a mesma apresenta plasticidade sináptica bidirecional por mecanismos de LTP e LTD (GODSIL et al, 2013). Esta é a principal eferência da formação hipocampal para o CPF, e tem se mostrado essencial para funções executivas, aprendizado, mecanismos mnemônicos e regulação da emoção (BANKS et al, 2015). Prejuízos nessa conectividade acarretam déficits cognitivos observados em doenças psiquiátricas, como esquizofrenia, depressão e estresse pós-traumático (GODSIL et al, 2013).…”