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Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation

Park, Eun Hye; Kao, Hsin-Yi; Jourdi, Hussam; van Dijk, Milenna T; Carrillo-Segura, Simón; Tunnell, Kayla W; Gutierrez, Jeffrey; Wallace, Emma J; Troy-Regier, Matthew; Radwan, Basma; Lesburguères, Edith; Alarcon, Juan Marcos; Fenton, André A
BACKGROUND/UNASSIGNED:Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. METHODS/UNASSIGNED:The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. RESULTS/UNASSIGNED:Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented PCP-induced discoordination and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR antagonist NVP-AAM077 unbalanced translation that engages the Akt, mTOR (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. CONCLUSIONS/UNASSIGNED:PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.
PMCID:10829677
PMID: 38298788
ISSN: 2667-1743
CID: 5627222

Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation

Park, Eun Hye; Kao, Hsin Yi; Jourdi, Hussam; van Dijk, Milenna T.; Carrillo-Segura, Simón; Tunnell, Kayla W.; Gutierrez, Jeffrey; Wallace, Emma J.; Troy-Regier, Matthew; Radwan, Basma; Lesburguères, Edith; Alarcon, Juan Marcos; Fenton, André A.
Background: Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. Methods: The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. Results: Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis"“dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented PCP-induced discoordination and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR antagonist NVP-AAM077 unbalanced translation that engages the Akt, mTOR (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. Conclusions: PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.
SCOPUS:85165317824
ISSN: 2667-1743
CID: 5549222

Diagnostic Challenges in Outpatient Stroke: Stroke Chameleons and Atypical Stroke Syndromes

Wallace, Emma J C; Liberman, Ava L
Failure to diagnose transient ischemic attack (TIA) or stroke in a timely fashion is associated with significant patient morbidity and mortality. In the outpatient or clinic setting, we suspect that patients with minor, transient, and atypical manifestations of cerebrovascular disease are most prone to missed or delayed diagnosis. We therefore detail common stroke chameleon symptoms as well as atypical stroke presentations, broadly review new developments in the study of diagnostic error in the outpatient setting, suggest practical clinical strategies for diagnostic error reduction, and emphasize the need for rapid consultation of stroke specialists when appropriate. We also address the role of psychiatric disease and vascular risk factors in the diagnostic evaluation and treatment of suspected stroke/TIA patients. We advocate incorporating diagnostic time-outs into clinical practice to assure that the diagnosis of TIA or stroke is considered in all relevant patient encounters after a detailed history and examination are conducted in the outpatient setting.
PMCID:8129915
PMID: 34017173
ISSN: 1176-6328
CID: 5241362

Race/Ethnic Disparities Publications in Neurological Journals During an Era of Heightened Awareness to Issues of Diversity, Equity and Inclusion [Meeting Abstract]

Esenwa, Charles; Patel, Nikunj; Wallace, Emma; Etienne, Mill; Ovbiagele, Bruce
ISI:000704705300197
ISSN: 0364-5134
CID: 5261372

Persistent modifications of hippocampal synaptic function during remote spatial memory

Pavlowsky, Alice; Wallace, Emma; Fenton, Andre A; Alarcon, Juan Marcos
A widely accepted notion for a process underlying memory formation is that learning changes the efficacy of synapses by the mechanism of synaptic plasticity. While there is compelling evidence of changes in synaptic efficacy observed after learning, demonstration of persistent synaptic changes accompanying memory has been elusive. We report that acquisition of a hippocampus and long-term potentiation dependent place memory persistently changes the function of CA1 synapses. Using extracellular recordings we measured CA3-CA1 and EC-CA1 synaptic responses and found robust changes in the CA3-CA1 pathway after memory training. Crucially, these changes in synaptic function lasted at least a month and coincided with the persistence of long-term place memories; the changes were only observed in animals that expressed robust memory, and not in animals with poor memory recall. Interestingly, our findings were observed at the level of populations of synapses; suggesting that memory formation recruits widespread synaptic circuits and persistently reorganizes their function to store information.
PMCID:5326703
PMID: 27568918
ISSN: 1095-9564
CID: 2517942

Compensation for PKMzeta in long-term potentiation and spatial long-term memory in mutant mice

Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong; Lesburgueres, Edith; Wallace, Emma Jane Claire; Tcherepanov, Andrew; Jothianandan, Desingarao; Hartley, Benjamin Rush; Pan, Ling; Rivard, Bruno; Farese, Robert V; Sajan, Mini P; Bergold, Peter John; Hernandez, Alejandro Ivan; Cottrell, James E; Shouval, Harel Z; Fenton, Andre Antonio; Sacktor, Todd Charlton
PKMzeta is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMzeta in PKMzeta-null mice. Two hypotheses can account for these findings. First, PKMzeta is unimportant for LTP or memory. Second, PKMzeta is essential for late-LTP and long-term memory in wild-type mice, and PKMzeta-null mice recruit compensatory mechanisms. We find that whereas PKMzeta persistently increases in LTP maintenance in wild-type mice, PKCiota/lambda, a gene-product closely related to PKMzeta, persistently increases in LTP maintenance in PKMzeta-null mice. Using a pharmacogenetic approach, we find PKMzeta-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMzeta-null mice without the target mRNA. Conversely, a PKCiota/lambda-antagonist disrupts late-LTP and spatial memory in PKMzeta-null mice but not in wild-type mice. Thus, whereas PKMzeta is essential for wild-type LTP and long-term memory, persistent PKCiota/lambda activation compensates for PKMzeta loss in PKMzeta-null mice.
PMCID:4869915
PMID: 27187150
ISSN: 2050-084x
CID: 2151862

Phencyclidine Causes Neural Discoordination and Cognitive Control Impairment by Dysregulating Protein Synthesis [Meeting Abstract]

Kao, Hsin-Yi; Dvorak, Dino; Park, Eunhye; Radwan, Basma; van Dijk, Milenna; Wallace, Emma; Troy-Regier, Matthew M; Zhong, Jun; Alarcon, Juan M; Fenton, Andre A
ISI:000334101801127
ISSN: 1873-2402
CID: 1015192

Storage of spatial information by the maintenance mechanism of LTP

Pastalkova, Eva; Serrano, Peter; Pinkhasova, Deana; Wallace, Emma; Fenton, Andre Antonio; Sacktor, Todd Charlton
Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not previously possible. Recently however, persistent phosphorylation by the atypical protein kinase C isoform, protein kinase Mzeta (PKMz), has been found to maintain late LTP in hippocampal slices. Here we show that a cell-permeable PKMz inhibitor, injected in the rat hippocampus, both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, the mechanism maintaining LTP sustains spatial memory.
PMID: 16931766
ISSN: 1095-9203
CID: 1710212