Excitability Of Prefrontal Cortex Neurons Research Articles

Systemic administration of lipopolysaccharide induces hyperexcitability of prelimbic neurons via modulation of sodium and potassium currents

In C57BL/6 J mice, systemic inflammation was induced by administering bacterial LPS (1 mg/kg) intraperitoneally. In response, animals exhibited hypokinesia, piloerection, and a slight decrease in body temperature accompanied by increased serum levels of the proinflammatory cytokine TNF-α. 24 h after the immunogenic challenge, acute cortical slices were prepared, and whole-cell patch-clamp recordings were performed in morphologically identified prelimbic neurons of the mice’s prefrontal cortex. Electrophysiologic alterations included changes in the kinetics parameters of the fast-inactivating sodium and slow-inactivating potassium currents. In current-clamp mode, our recordings revealed alterations in several conductances that shape the intrinsic excitability of prelimbic neurons. The action potential exhibited changes in latency, amplitude, and the rheobase current to elicit firing discharge. Likewise, phase plots of the action potentials uncovered alterations in the repetitive firing of prelimbic neurons. Consistent with these changes, the afterhyperpolarization conductance and the slowly decaying, calcium‐dependent after-hyperpolarization current that follows an action potential were decreased in response to systemic LPS. Our data demonstrate that immune activation alters the ionic currents that shape the intrinsic excitability and predicts dysregulation of non-synaptic forms of neuronal plasticity modulated by the intrinsic excitability of prefrontal cortex neurons.

Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors.

Attention-deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder in childhood. Currently available ADHD drugs include the psychostimulants methylphenidate (MPH) and D-amphetamine (D-AMP), acting on norepinephrine and dopamine transporters/release, and atomoxetine (ATX), a selective norepinephrine uptake inhibitor. Recent evidence suggests an involvement of glutamate neurotransmission in the pathology and treatment of ADHD, via mechanisms to be clarified. We have investigated how ADHD drugs could modulate, through interaction with catecholamine receptors, basal and glutamate-induced excitability of pyramidal neurons in the prefrontal cortex (PFC), a region which plays a major role in control of attention and impulsivity. We have used the technique of extracellular single-unit recording in anaesthetised rats coupled with microiontophoresis. Both MPH (1-3mg/kg) and D-AMP (1-9mg/kg) increased the firing activity of PFC neurons in a dopamine D1 receptor-dependent manner. ATX administration (1-6mg/kg) also increased the firing of neurons, but this effect is not significantly reversed by D1 (SCH 23390) or alpha1 (prazosin) receptor antagonists but potentiated by alpha2 antagonist (yohimbine). All drugs induced a clear potentiation of the excitatory response of PFC neurons to the microiontophoretic application of the glutamate agonist N-methyl-D-aspartate (NMDA), but not to the glutamate agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). The potentiating effect of D-AMP on NMDA-induced activation of PFC neurons was partially reversed or prevented by dopamine D1 receptor blockade. Our data shows that increase in excitability of PFC neurons in basal conditions and via NMDA receptor activation may be involved in the therapeutic response to ADHD drugs.

Dopamine and Serotonin Interactively Modulate Prefrontal Cortex Neurons In Vitro

Dopamine (DA) and serotonin (5-HT) are released in cortex under similar circumstances, and many psychiatric drugs bind to both types of receptors, yet little is known about how they interact. To characterize the nature of these interactions, the current study used in vitro patch-clamp recordings to measure the effects of DA and/or 5-HT on pyramidal cells in layer V of the medial prefrontal cortex. Either DA or 5-HT applied in isolation increased the evoked excitability of prefrontal cortex neurons, as shown previously. Coapplication of DA and 5-HT produced either a larger increase in excitability than when either was given alone or a significant decrease that was never observed when either was given alone. Dopamine or 5-HT also "primed" neurons to respond in an exaggerated manner to the subsequent application of the other monoamine. These data reveal the unappreciated interactive nature of neuromodulation in cortex by showing that the combined effects of DA and 5-HT can be different from their effects recorded in isolation. On the basis of these findings, we present a theory of how DA and 5-HT might synergistically modulate cortical circuits during various tasks.

Dopamine D1/5 Receptor-Mediated Long-Term Potentiation of Intrinsic Excitability in Rat Prefrontal Cortical Neurons: Ca2+-Dependent Intracellular Signaling

Prefrontal cortex (PFC) dopamine D1/5 receptors modulate long- and short-term neuronal plasticity that may contribute to cognitive functions. Synergistic to synaptic strength modulation, direct postsynaptic D1/5 receptor activation also modulates voltage-dependent ionic currents that regulate spike firing, thus altering the neuronal input-output relationships in a process called long-term potentiation of intrinsic excitability (LTP-IE). Here, the intracellular signals that mediate this D1/5 receptor-dependent LTP-IE were determined using whole cell current-clamp recordings in layer V/VI rat pyramidal neurons from PFC slices. After blockade of all major amino acid receptors (V(hold) = -65 mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist SKF81297 (0.2-50 microM) induced LTP-IE, as shown by a prolonged (>40 min) increase in depolarizing pulse-evoked spike firing. Pretreatment with the D1/5 antagonist SCH23390 (1 microM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The SKF81297-induced LTP-IE was significantly attenuated by Cd(2+), [Ca(2+)](i) chelation, by inhibition of phospholipase C, protein kinase-C, and Ca(2+)/calmodulin kinase-II, but not by inhibition of adenylate cyclase, protein kinase-A, MAP kinase, or L-type Ca(2+) channels. Thus this form of D1/5 receptor-mediated LTP-IE relied on Ca(2+) influx via non-L-type Ca(2+) channels, activation of PLC, intracellular Ca(2+) elevation, activation of Ca(2+)-dependent CaMKII, and PKC to mediate modulation of voltage-dependent ion channel(s). This D1/5 receptor-mediated modulation by PKC coexists with the previously described PKA-dependent modulation of K(+) and Ca(2+) currents to dynamically regulate overall excitability of PFC neurons.

Electrophysiological effects of acute and chronic olanzapine and fluoxetine in the rat prefrontal cortex

Since the prefrontal cortex (PFC) is thought to play an important role in depression and schizophrenia, we studied the effects of fluoxetine and olanzapine on PFC neurons in rats using extracellular, in vivo recordings. Acute or 5-day administration of olanzapine (1–10 mg/kg, iv or 20 mg/kg, sc) did not change the firing rate of PFC neurons. However, a 21-day treatment with olanzapine (20 mg/kg per day, sc) significantly increased the firing rate of PFC neurons and increased their responsiveness to the iontophoretic administration of the GABA A antagonist bicuculline. Acute administration of fluoxetine (10 mg/kg, iv) also did not change the firing rate of PFC neurons. However, a 21-day treatment with fluoxetine (10 mg/kg per day) significantly decreased the firing rate of PFC neurons and decreased their responsiveness to the iontophoretic administration of bicuculline. Co-administration of olanzapine (10 mg/kg per day, sc) during the last 5 days of a 21-day fluoxetine treatment (10 mg/kg per day) prevented the suppression of firing and decreased responsiveness to the iontophoretic administration of bicuculline of PFC neurons. In conclusion, chronic, but not acute, olanzapine treatment significantly enhanced the firing and excitability of PFC neurons. In addition, chronic, but not acute, fluoxetine treatment significantly suppressed the firing and excitability of PFC neurons. Further, short-term olanzapine treatment attenuated the suppression of firing and excitability of PFC neurons induced by chronic fluoxetine treatment. These effects of olanzapine, fluoxetine, and the olanzapine/fluoxetine combination in the PFC may play an important role in the beneficial therapeutic effect of these compounds in schizophrenia and depression and may have implications for the treatment of treatment-resistant depression.

Stimulation of D1-type dopamine receptors enhances excitability in prefrontal cortical pyramidal neurons in a state-dependent manner.

Prefrontal cortex neurons recorded in vivo exhibit bistable activity states, consisting of a depolarized phase (-55mV) and a hyperpolarized phase (-85mV). These "up" and "down" states have durations ranging from 800ms to 1s and a periodicity of approximately 1Hz. This study examines the state-dependency of prefrontal cortical neuron responses to dopamine, in which the bistable-state was approximated in vitro by intracellular current injection. At resting membrane potential (n=10), dopamine caused a significant depolarization of the membrane potential without altering any of the other electrophysiological characteristics tested. In contrast, both dopamine (30 microM, 5min) and the D1 receptor agonist SKF 38393 (5 and 10 microM) increased cell excitability when the cell was in the depolarized state (i.e., -55mV) but not the hyperpolarized state (i.e., -85 mV; n=10). This increase in excitability was accompanied by a decrease in the rheobase current. The SKF 38393-enhanced excitability was dose-dependent and could be blocked by bath administration of the D1 receptor antagonist SCH 23390 (5 and 10 microM). Administration of the GABA antagonist bicuculline (7 microM) plus the N-methyl-D-aspartate channel blocker CPP (10 microM) produced an additional increase in the excitability of prefrontal cortex neurons that was not dependent on the membrane potential. From these data we suggest that dopamine exerts state-dependent modulatory effects on the excitability of neurons in deep layers of the prefrontal cortex.