Activation of Metabotropic Glutamate 2/3 Receptors Reverses the Effects of NMDA Receptor Hypofunction on Prefrontal Cortex Unit Activity in Awake Rats

2005 ◽  
Vol 93 (4) ◽  
pp. 1989-2001 ◽  
Author(s):  
Houman Homayoun ◽  
Mark E. Jackson ◽  
Bita Moghaddam
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptor ◽  
Firing Rate ◽  
Spike Activity ◽  
Systemic Exposure ◽  
Nmda Antagonist ◽  
Laboratory Animals ◽  
Cellular Mechanisms ◽  
Physiological Basis ◽  
Metabotropic Glutamate

Systemic exposure to N-methyl-d-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)–dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.

Interaction of Dopamine D1 and NMDA Receptors Mediates Acute Clozapine Potentiation of Glutamate EPSPs in Rat Prefrontal Cortex

2002 ◽  
Vol 87 (5) ◽  
pp. 2324-2336 ◽  
Author(s):  
Long Chen ◽  
Charles R. Yang
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Ampa Receptors ◽  
Nmda Receptor Antagonist ◽  
D1 Receptor ◽  
Resting Membrane Potential ◽  
Cellular Mechanisms ◽  
Cognitive Improvement

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V–VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 μM bicuculline) evoked mixed [AMPA/kainate and N-methyl-d-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 μM) potentiated polysynaptically mediated evoked EPSPs ( V Hold = −65 mV), or reversed EPSPs (rEPSP, V Hold = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca2+]O(7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 μM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 μM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 μM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 μM) enhanced the frequency, and the number of low-amplitude (5–10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 μM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.

Computational Studies of Gain Modification by Serotonin in Pyramidal Neurons of Prefrontal Coxtex

2006 ◽  
Author(s):  
Guoshi Li ◽  
Harvey C. Cline ◽  
Pierre Blier ◽  
Satish Nair
Keyword(s):  
Prefrontal Cortex ◽  
Firing Rate ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Input Resistance ◽  
Square Root ◽  
Gain Modulation ◽  
Cellular Mechanisms ◽  
Brain Functions ◽  
A Current

Serotonin (5-HT) is widely implicated in brain functions and diseases, but the cellular mechanisms underlying 5-HT functions in the brain are not well understood (Zhang and Arsenault, 2005). Recent experiments (Zhang and Arsenault, 2005) have shown that 5-HT substantially increased the slope (gain) of the firing rate current (F-I) curve in layer 5 pyramidal neurons of the rat prefrontal cortex and this effect was limited to the range of firing rate (0-10 Hz) that is known to behaviourally relevant. Furthermore, it was found that 5-HT mediated gain increase was due to a reduction of the afterhyperpolarization (AHP) and an induction of the slow afterdepolarization (ADP), regardless of changes in the membrane potential, the input resistance or the properties of action potentials. To investigate this frequency-dependent gain modulation of 5-HT on the prefrontal cortex neurons, conductance-based Hodgkin-Huxley type models of the regular spiking (RS) cells in the prefrontal cortex are developed using a step by step approach. We first show that a model with an A current displays a square-root form F-I curve with higher slope at low frequency. However, for the same range of current injection steps used in experiment, the frequency range goes beyond 20 Hz, suggesting the presence of other hyperpolarizing currents in the model. As suggested by the experiment (Zhang and Arsenault, 2005), AHP currents (fast AHP, medium AHP and slow AHP) are included in the model to simulate 5-HT effect. Simulations show that AHP currents effectively linearize the F-I curve and decrease the slope of F-I curve in general, thus reducing the neuronal excitability. Since the slow AHP current is a target of 5-HT, the strength of this current is reduced gradually and the F-I curves are plotted together for comparison. The results indicate that with decreasing slow AHP strength, the current thresholds for repetitive spiking decreases and the slopes of the F-I curves increase in general. A square-root form F-I curve is not evident until the slow AHP current is blocked completely. This suggests that the medium AHP current also play a role in linearizing the F-I curve besides the slow AHP current. Based on current findings, a full model with both A current and AHP currents is being constructed to match the experimental data more closely so the mechanism of 5-HT on gain modulation of prefrontal cortical neurons can be better understood.

scholarly journals Developmental up-regulation of NMDA receptors in the prefrontal cortex and hippocampus of mGlu5 receptor knock-out mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Tiziana Imbriglio ◽  
Remy Verhaeghe ◽  
Nico Antenucci ◽  
Stefania Maccari ◽  
Giuseppe Battaglia ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Adult Life ◽  
Developmental Time ◽  
Postnatal Life ◽  
Developmental Studies ◽  
Knock Out ◽  
Nmda Receptor Subunits ◽  
The Impact

AbstractmGlu5 metabotropic glutamate receptors are highly expressed and functional in the early postnatal life, and are known to positively modulate NMDA receptor function. Here, we examined the expression of NMDA receptor subunits and interneuron-related genes in the prefrontal cortex and hippocampus of mGlu5−/− mice and wild-type littermates at three developmental time points (PND9, − 21, and − 75). We were surprised to find that expression of all NMDA receptor subunits was greatly enhanced in mGlu5−/− mice at PND21. In contrast, at PND9, expression of the GluN2B subunit was enhanced, whereas expression of GluN2A and GluN2D subunits was reduced in both regions. These modifications were transient and disappeared in the adult life (PND75). Changes in the transcripts of interneuron-related genes (encoding parvalbumin, somatostatin, vasoactive intestinal peptide, reelin, and the two isoforms of glutamate decarboxylase) were also observed in mGlu5−/− mice across postnatal development. For example, the transcript encoding parvalbumin was up-regulated in the prefrontal cortex of mGlu5−/− mice at PND9 and PND21, whereas it was significantly reduced at PND75. These findings suggest that in mGlu5−/− mice a transient overexpression of NMDA receptor subunits may compensate for the lack of the NMDA receptor partner, mGlu5. Interestingly, in mGlu5−/− mice the behavioral response to the NMDA channel blocker, MK-801, was significantly increased at PND21, and largely reduced at PND75. The impact of adaptive changes in the expression of NMDA receptor subunits should be taken into account when mGlu5−/− mice are used for developmental studies.

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