567. NMDA-mediated neurophysiologic deficits in schizophrenia

Javitt, Daniel C.; Lindsley, Robert W.; Schroeder, C.

doi:10.1016/s0006-3223(00)00869-6

Cited by 11 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NMDA receptor signaling – PFC network firing during working memory depends on glutamate actions at NMDA receptors on pyramidal cell spines (Arnsten et al, 2010 and Wang and Arnsten, unpublished). The reduction in NMDA receptor signaling in schizophrenia is widely discussed, and may arise from a number of factors, including genetic insults to such NMDA regulatory proteins as NRG1 and dysbindin (reviewed in Krystal et al, 2003; Ross et al, 2006; Javitt, 2010; Kristiansen et al, 2010). Reduced NMDA receptor signaling can lead to spine shrinkage and loss (Hayashi‐Takagi et al, 2010), suggesting that both functional and architectural dysfunction can arise from these insults (see above).…”

Section: Genetic Insults To “Molecular Brakes” On Stress Pathways In ...mentioning

confidence: 99%

Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia

Arnsten

2011

Intl J of Devlp Neuroscience

156

130

View full text Add to dashboard Cite

The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC networks create our “mental sketch pad”, and PFC dysfunction contributes to symptoms such as cognitive deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for accurate representational knowledge (i.e. working memory). The strength of pyramidal cell network connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a process called Dynamic Network Connectivity (DNC). DNC proteins such as HCN channels are concentrated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells are strengthened by noradrenergic alpha-2A inhibition of cAMP-HCN channel signaling, and sculpted by dopamine D1-cAMP-HCN channel weakening of inappropriate inputs. However, with stress exposure, high levels of cAMP-HCN channel signaling produces a collapse in network firing. With chronic stress exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Importantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response, are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with already vulnerable circuitry to cause spine loss and the descent into illness.

show abstract

Section: Genetic Insults To “Molecular Brakes” On Stress Pathways In ...mentioning

confidence: 99%

Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia

Arnsten

2011

Intl J of Devlp Neuroscience

156

130

View full text Add to dashboard Cite

show abstract

“…One potential pathophysiological mechanism underlying the progression of schizophrenia seems to depend on dysfunction in the N-methyl-d-aspartate glutamate receptor (NMDAR) [ 43 ]. The NMDA model of schizophrenia originated from the observation that NMDA antagonists, like Ket, can induce memory impairment.…”

Section: Discussionmentioning

confidence: 99%

Berberine improves inhibitory avoidance memory impairment of Toxoplasma gondii-infected rat model of ketamine-induced schizophrenia

Gholizadeh,

Dalimi,

Ghaffarifar

et al. 2023

BMC Complement Med Ther

View full text Add to dashboard Cite

Background Memory impairment caused by Toxoplasma gondii infection has been documented. Berberine (BRB) is well known for its enhancing effects on memory and has shown promising results. However, the impact of BRB on T. gondii infection and schizophrenia-induced consolidation and reconsolidation memory impairment is still unclear. Here; we examined the effect of BRB on the inhibitory avoidance (IA) memory consolidation and reconsolidation impairment induced by T. gondii infection, and ketamine (Ket) as a pharmacological model of schizophrenia. Also; the brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC) and hippocampus were analyzed. Methods Rats were infected with T. gondii RH strain or received Ket (30 mg/kg/day) intraperitoneally (i.p) for at least five consecutive days (as the model of schizophrenia). Then followed by oral administration with BRB (25 mg/kg/day) for five days. Finally, the IA memory retention test was examined 48 post-conditioning, and BDNF was measured. Results Results indicated IA memory impairment in T. gondii-infected animals since lower step-through latency (STL) was observed than in control animals. We found significant (P = 0.01, P = 0.001) elevations in STL and a significant decrease (P = 0.001) in total time spent in the dark area following BRB administration in infected and Ket-treated rats, indicating improvement (increased STL) in consolidation and reconsolidation memory. Moreover, BDNF levels were reduced (P = 0.01) in the hippocampus and mPFC regions of both T. gondii- infected and Ket-induced groups, which remarkably enhanced after BRB treatment. Furthermore; we found that BRB administration notably increased the mPFC BDNF levels in mPFC (P < 0.01) and hippocampus (P = 0.001) in the Ket-treated and rats infected with T. gondii. Conclusion Taken together; BRB may be a valuable preclinical treatment for improving memory impairment through BDNF expression in PFC and hippocampus, therefore; BRB is suggested for memory disturbances induced by T. gondii infection.

show abstract

“…However, the molecular mechanisms that control NMDAR plasticity and determine its direction remain unclear. A better understanding of these mechanisms is important since NMDAR dysregulation has been implicated in several brain disorders ( Lau and Zukin, 2007 ), including schizophrenia ( Javitt, 2010 ), autism spectrum disorder ( Won et al, 2012 ), addiction ( Borgland et al, 2006 ) and neurodegenerative diseases such as Alzheimer’s ( Liu et al, 2019 ) and Parkinson’s disease ( Gardoni et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Target cell-specific plasticity rules of NMDA receptor-mediated synaptic transmission in the hippocampus

Lutzu

Alviña

Puente

et al. 2023

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Long-term potentiation and depression of NMDA receptor-mediated synaptic transmission (NMDAR LTP/LTD) can significantly impact synapse function and information transfer in several brain areas. However, the mechanisms that determine the direction of NMDAR plasticity are poorly understood. Here, using physiologically relevant patterns of presynaptic and postsynaptic burst activities, whole-cell patch clamp recordings, 2-photon laser calcium imaging in acute rat hippocampal slices and immunoelectron microscopy, we tested whether distinct calcium dynamics and group I metabotropic glutamate receptor (I-mGluR) subtypes control the sign of NMDAR plasticity. We found that postsynaptic calcium transients (CaTs) in response to hippocampal MF stimulation were significantly larger during the induction of NMDAR-LTP compared to NMDAR-LTD at the MF-to-CA3 pyramidal cell (MF-CA3) synapse. This difference was abolished by pharmacological blockade of mGluR5 and was significantly reduced by depletion of intracellular calcium stores, whereas blocking mGluR1 had no effect on these CaTs. In addition, we discovered that MF to hilar mossy cell (MF-MC) synapses, which share several structural and functional commonalities with MF-CA3 synapses, also undergoes NMDAR plasticity. To our surprise, however, we found that the postsynaptic distribution of I-mGluR subtypes at these two synapses differ, and the same induction protocol that induces NMDAR-LTD at MF-CA3 synapses, only triggered NMDAR-LTP at MF-MC synapses, despite a comparable calcium dynamics. Thus, postsynaptic calcium dynamics alone cannot predict the sign of NMDAR plasticity, indicating that both postsynaptic calcium rise and the relative contribution of I-mGluR subtypes likely determine the learning rules of NMDAR plasticity.

show abstract

567. NMDA-mediated neurophysiologic deficits in schizophrenia

Cited by 11 publications

References 0 publications

Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia

Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia

Berberine improves inhibitory avoidance memory impairment of Toxoplasma gondii-infected rat model of ketamine-induced schizophrenia

Target cell-specific plasticity rules of NMDA receptor-mediated synaptic transmission in the hippocampus

Contact Info

Product

Resources

About