Firing Activity Of Pyramidal Neurons Research Articles

Short-term hyperoxia-induced functional and morphological changes in rat hippocampus.

Excess oxygen (O2) levels may have a stimulating effect, but in the long term, and at high concentrations of O2, it is harmful to the nervous system. The hippocampus is very sensitive to pathophysiological changes and altered O2 concentrations can interfere with hippocampus-dependent learning and memory functions. In this study, we investigated the hyperoxia-induced changes in the rat hippocampus to evaluate the short-term effect of mild and severe hyperoxia. Wistar male rats were randomly divided into control (21% O2), mild hyperoxia (30% O2), and severe hyperoxia groups (100% O2). The O2 exposure lasted for 60 min. Multi-channel silicon probes were used to study network oscillations and firing properties of hippocampal putative inhibitory and excitatory neurons. Neural damage was assessed using the Gallyas silver impregnation method. Mild hyperoxia (30% O2) led to the formation of moderate numbers of silver-impregnated "dark" neurons in the hippocampus. On the other hand, exposure to 100% O2 was associated with a significant increase in the number of "dark" neurons located mostly in the hilus. The peak frequency of the delta oscillation decreased significantly in both mild and severe hyperoxia in urethane anesthetized rats. Compared to normoxia, the firing activity of pyramidal neurons under hyperoxia increased while it was more heterogeneous in putative interneurons in the cornu ammonis area 1 (CA1) and area 3 (CA3). These results indicate that short-term hyperoxia can change the firing properties of hippocampal neurons and network oscillations and damage neurons. Therefore, the use of elevated O2 concentration inhalation in hospitals (i.e., COVID treatment and surgery) and in various non-medical scenarios (i.e., airplane emergency O2 masks, fire-fighters, and high altitude trekkers) must be used with extreme caution.

A rate-limiting step in antidepressants onset: Excitation of glutamatergic pyramidal neurons in medial prefrontal cortex of rodents

Although clinical antidepressants have varied mechanisms of action, it remains unclear whether they may have a common mechanism underlying their antidepressant effects. We investigated the behavioral effects of five different antidepressants (differing in target, chemical structure, and rate of onset) and their effects on the firing activities of glutamatergic pyramidal neurons in the medial prefrontal cortex (mPFC) using the forced swimming test (FST) and electrophysiological techniques (in vivo). We employed fiber photometry recordings to validate the effects of antidepressants on the firing activity of pyramidal neurons. Additionally, multichannel electrophysiological recordings were conducted in mice exhibiting depressive-like behaviors induced by chronic restraint stress (CRS) to investigate whether antidepressants exert similar effects on pyramidal neurons in depressed mice. Behavioral tests were utilized for evaluating the depression model. We found that fluoxetine, duloxetine, vilazodone, YL-0919, and ketamine all increase the firing activities of glutamatergic pyramidal neurons (at least 57%) while exerting their initial onset of antidepressant effects. Fiber photometry revealed an increase in the calcium activity of pyramidal neurons in the mPFC at the onset of antidepressant effects. Furthermore, a significant reduction was observed in the firing activity of pyramidal neurons in the mPFC of CRS-exposed mice, which was reversed by antidepressants. Taken together, our findings suggested that five pharmacologically distinct classes of antidepressants share the common ability to increase the firing activity of pyramidal neurons, just different time, which might be a rate-limiting step in antidepressants onset. The study contributes to the body of knowledge of the mechanisms underlying antidepressant effects and paves the way for developing rapid-acting antidepressants.

Environmental Enrichment Improves the Recognition Memory in Adult Mice Following Social Isolation via Downregulation of Kv4.2 Potassium Channels.

Recognition memory is a cognitive process that enables us to distinguish familiar objects and situations from new items, which is essential for mammalian survival and adaptation to a changing environment. Social isolation (SI) has been implicated as a detrimental factor for recognition memory. The medial prefrontal cortex (mPFC) has been shown to carry information concerning the relative familiarity of individual stimuli, and modulating neuronal function in this region may contribute to recognition memory. The present study aimed to investigate the neuronal mechanisms in the mPFC of environmental enrichment (EE) on recognition memory in adult mice following SI. Mice were assigned into three groups: control, SI, and SI + EE groups. Novel location recognition (NLR) and novel object recognition (NOR) tests were performed to evaluate the recognition memory. The levels of Kv4 channels were assessed by qRT-PCR and western blotting. The effects of SI and SI + EE on the excitability of pyramidal neurons in the mPFC were measured using whole-cell recording. We found that SI led to a reduction in the excitability of pyramidal neurons. Specifically, we have identified that the reduction in the firing activity of pyramidal neurons resulted from alterations in the function and expression of Kv4.2 channels. Furthermore, EE regulated Kv4.2 channels, normalized the activity of pyramidal neurons, and restored the behavioral deficits following SI. Thus, the roles of Kv4.2 channels in excitability of pyramidal neurons suggest that the Kv4.2 channels present a promising therapeutic target for recognition memory impairment.

Dopamine D1 receptor in the medial prefrontal cortex mediates anxiety-like behaviors induced by blocking glutamatergic activity of the ventral hippocampus in rats

The medial prefrontal cortex (mPFC) receives direct and indirect projections from the ventral hippocampus (VH) and plays an important role in the regulation of anxiety. However, the effect of the mPFC dopamine D1 receptor on anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH has not been described. Here, we examined the effects of SKF38393, a selective dopamine D1 receptor agonist, on anxiety-like behaviors induced by NMDA receptor inhibition in the VH and neuron firing activity of mPFC. Injection of MK-801 (6 μg/0.5 μl) into the VH produced anxiety-like behaviors in the elevated plus maze and open field tests, increased the firing activity of pyramidal neurons in the mPFC, and decreased the level of dopamine in the mPFC. Injection of SKF38393 (0.5 μg/0.5 μl) into the mPFC produced anxiolytic effects, and normalized the hyperactive firing activity of mPFC pyramidal neurons induced by MK-801, whereas in both normal and anxiety-like rats caused by MK-801, injection of SKF38393 into the mPFC decreased the firing activity of mPFC interneurons but did not affect the dopamine content in the mPFC. The present data demonstrate that decreased D1 receptor activation in the mPFC may mediate anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH. The balance of D1 receptor activity between pyramidal neurons and interneurons is a crucial factor in maintaining normal conditions, and inhibitory glutamatergic activity in the VH induces hyperactivity of mPFC pyramidal neurons through decreases in dopamine release and in the amount of D1 receptor activation on mPFC pyramidal neurons, which may be a critical factor for anxiety disorders.

ProBDNF and p75NTR Control Excitability and Persistent Firing of Cortical Pyramidal Neurons.

Persistent firing of entorhinal cortex (EC) pyramidal neurons is required for working memory. We report here that pro-brain-derived neurotrophic factor (proBDNF) activates p75NTR to induce a Rac1-dependent and phosphatidylinositol 4,5-bisphosphate-dependent signaling cascade that suppresses persistent activity. Conversely, using loss-of-function approaches, we find that endogenous proBDNF or p75NTR activation strongly decreases pyramidal neuron excitability and persistent firing, suggesting that a physiological role of this proBDNF-p75NTR cascade may be to regulate working memory in vivo. Consistent with this, mice rendered null for p75NTR during adulthood show improvements in working memory but also display an increased propensity for severe seizures. We propose that by attenuating EC network performance, the proBDNF-p75NTR signaling cascade reduces the probability of epileptogenesis.

Modulation of the Antidepressant-Like Effects of Sustained Administration of Carisbamate and Lamotrigine on Monoaminergic Systems: Electrophysiological Studies in the Rat Brain

Carisbamate and lamotrigine are anticonvulsants that act on neuronal voltage-gated sodium channels. Carisbamate has shown antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents, which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg daily), or lamotrigine (25 mg/kg daily). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus norepinephrine, and ventral tegmental area dopamine (DA) neurons was decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing, and this effect was abolished by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited a significant increase in tonic activation of hippocampus 5-HT1A receptors, as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635 (N-{2-[4(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). This finding reveals an increase in the 5-HT level that may be attributed to a desensitization of the terminal 5-HT1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action and may contribute to the antidepressant-like effect of carisbamate in the forced swim test and the antidepressant properties of lamotrigine.

The pyramidal neurons in the medial prefrontal cortex show decreased response to 5-hydroxytryptamine-3 receptor stimulation in a rodent model of Parkinson's disease

In the present study, effect of SR 57227A, a selective 5-hydroxytryptamine-3 (5-HT3) receptor agonist, on the firing activity of pyramidal neurons in the medial prefrontal cortex (mPFC) was studied in normal rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Systemic administration of SR 57227A (40–640μg/kg, i.v.) decreased the mean firing rate of pyramidal neurons in normal and the lesioned rats. This inhibition was significant only at doses higher than 320μg/kg and 640μg/kg in normal and the lesioned rats, respectively, and was reversed by i.v. administration of 5-HT3 receptor antagonist tropisetron or GABAA receptor antagonist bicuculline. Furthermore, local application of SR 57227A (0.01μg) in the mPFC inhibited the firing rate of pyramidal neurons in normal rats while having no effect on firing rate in the lesioned rats. The i.v. administration of bicuculline excited the pyramidal neurons in normal rats, and then local application of SR 57227A did not alter the mean firing rate of these neurons. However, these two drugs did not affect the activity of the pyramidal neurons in the lesioned rats. We conclude that activation of 5-HT3 receptors inhibited pyramidal neurons in the mPFC of normal rats via GABAergic interneurons, and degeneration of the nigrostriatal pathway decreased response of the pyramidal neurons to SR 57227A, suggesting the dysfunction of 5-HT3 receptors and/or down-regulation of the expression on GABAergic interneurons in the lesioned rats.

Noradrenergic lesion of the locus coeruleus increases the firing activity of the medial prefrontal cortex pyramidal neurons and the role of α 2-adrenoceptors in normal and medial forebrain bundle lesioned rats

Degeneration of noradrenergic neurons in the locus coeruleus (LC) and dysfunction of the prefrontal cortex were regarded as playing a specific role in the occurrence of non-motor symptoms in Parkinson's disease. The present study examined the spontaneous firing rate and firing pattern of medial prefrontal cortex (mPFC) pyramidal neurons, and effects of α 2-adrenoceptor agonist UK-14,304 and antagonist yohimbine on the neuronal activity in rats with 6-hydroxydopamine lesions of the LC, medial forebrain bundle (MFB) and with combined MFB and LC lesions. The firing rate of mPFC pyramidal neurons in rats with lesions of the LC and with combine LC and MFB lesions is significantly higher than that of normal and MFB-lesioned rats and the firing pattern of these neurons in rats with lesions of the LC and with combine LC and MFB lesions also changed significantly towards more regular compared with normal and MFB-lesioned rats. The local administration of UK-14,304 in the mPFC inhibited the firing activity of the pyramidal neurons in normal rats and rats with lesions of the LC, MFB and with combined LC and MFB lesions, while yohimbine increased the firing activity of the pyramidal neurons. These results indicate that the lesions of the LC lead to hyperactivity of mPFC pyramidal neurons in normal and MFB-lesioned rats, and the postsynaptic α 2-adrenoceptors may partially mediate the inhibitory effects of LC-noradrenergic system on the firing activity of pyramidal neurons in the mPFC, suggesting that LC-noradrenergic system plays an important role in the functional disorders of mPFC in Parkinson's disease.

In vivo effects of activation and blockade of 5-HT 2A/2C receptors in the firing activity of pyramidal neurons of medial prefrontal cortex in a rodent model of Parkinson's disease

In the present study, we examined changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC), and the effects of 5-HT 2A/2C receptor agonist DOI and antagonist ritanserin on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta by using extracellular recording. The unilateral lesion of the nigrostriatal pathway significantly increased the mean firing rate of pyramidal neurons compared to sham-operated rats, and the firing pattern of these neurons also changed significantly towards a more bursty one. Systemic administration of DOI (20–320 μg/kg, i.v.) increased the mean firing rate of pyramidal neurons in sham-operated and the lesioned rats. The excitation was significant only at doses higher than 160 μg/kg and 320 μg/kg in sham-operated and the lesioned rats, respectively. In addition, the local application of DOI, 5 μg, in mPFC inhibited the firing rate of pyramidal neurons in sham-operated rats, while having no effect on firing rate in the lesioned rats. After treatment with GABA A receptor antagonist picrotoxinin, the local application of DOI, at the same dose, increased the mean firing rate of the neurons in sham-operated rats; however, DOI did not alter the firing activity of the neurons in the lesioned rats. These results indicate that the lesion of the nigrostriatal pathway leads to hyperactivity of pyramidal neurons in mPFC, and the decreased response of pyramidal neurons to DOI, suggesting dysfunction of 5-HT 2A and 5-HT 2C receptors on pyramidal neurons and GABAergic interneurons in the 6-OHDA-lesioned rats.

The firing activity of pyramidal neurons in medial prefrontal cortex and their response to 5-hydroxytryptamine-1A receptor stimulation in a rat model of Parkinson's disease

The changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC) and the effects of selective 5-hydroxytryptamine-1A (5-HT1A) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the firing activity of the neurons were studied in sham-lesioned rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc increased the firing rate of pyramidal neurons significantly compared to sham-lesioned rats, and the firing pattern of these neurons also changed significantly towards a more burst-firing. The systemic administration of 8-OH-DPAT at doses in the range of 0.5–128 μg/kg showed an excitatory-inhibitory effect on the firing rate of pyramidal neurons in mPFC of sham-lesioned rats. At lower doses, 0.5–32 μg/kg, it evoked excitation of the neurons, and at a high dose, i.e. 128 μg/kg, inhibited the activity of the neurons. In contrast to sham-lesioned rats, 8-OH-DPAT, at the same doses, showed no excitatory effect in the lesioned rats although the inhibitory phase of the effect of 8-OH-DPAT on the firing rate of pyramidal neurons in mPFC was still present. Furthermore, the local application of 8-OH-DPAT, 5 μg, in mPFC inhibited the firing rate of pyramidal neurons in sham-lesioned rats, while having no effect on firing rate in the lesioned rats. The excitatory or inhibitory effects of 8-OH-DPAT were reversed by WAY-100635, indicating that these effects are mediated by 5-HT1A receptor. Altogether, these results indicate that the lesion of the SNc leads to hyperactivity of pyramidal neurons in mPFC and the abnormality of response of these neurons to 5-HT1A receptor stimulation, suggesting that mPFC may be involved in the pathophysiology of the psychiatric disturbance of Parkinson's disease.

Effect of long-term administration of the antidepressant drug milnacipran on serotonergic and noradrenergic neurotransmission in the rat hippocampus

The effect of a long-term administration of the antidepressant milnacipran on the function of the serotonergic (5-HT) and noradrenergic (NE) systems was studied using single cell recording of CA3 hippocampal pyramidal cells in chloral hydrate-anesthetized male Sprague–Dawley rats, and in vitro [ 3H]5-HT release measurement from hippocampal slices. The sensitivity of neither the extrasynaptic nor that of the postsynaptic 5-HT 1A receptors of the pyramidal neurons was altered, as indicated by their unchanged responsiveness to the microiontophoretic application of 5-HT, and by the unchanged effect of the electrical stimulation at low frequency of the ascending 5-HT bundle, respectively. Increasing the frequency of stimulation (from 1 to 5 Hz) decreased its efficacy in control rats; the milnacipran treatment abolished this phenomenon. This cannot be attributed to a desensitisation of the terminal 5-HT 1B autoreceptor, since the suppressive effect of 5-HT agonist 5-carboxyamidotryptamine on [ 3H]5-HT release was enhanced in milnacipran-treated rats. As for the NE system, the unchanged suppressing effect of microiontophoretic applications of NE and that of the 5 Hz stimulation in the locus coeruleus (LC) on the firing activity of pyramidal neurons indicates that the milnacipran treatment not altered the sensitivity of extrasynaptic α 2- and postsynaptic α 1-adrenergic receptors on pyramidal cells, as well as that of the presynaptic α 2-autoreceptor on NE terminals. The decreased inhibitory effect of NE on the [ 3H]5-HT release in milnacipran-treated rats revealed that this treatment results in a desensitisation of the presynaptic α 2-heteroreceptor located on serotonergic terminals. Taken together with the decreased suppressive effect of a low frequency of stimulation of the NE tract, the present results suggest that long-term milnacipran treatment enhances the efficacy of the 5-HT and reduces that of the NE neurotransmission.

Electrophysiological characterization of adrenoceptors in the rat dorsal hippocampus. III. Evidence for the physiological role of terminalα 2-adrenergic autoreceptors

The present electrophysiological studies were undertaken to assess the role of terminalα 2-adrenergic autoreceptors in regulating noradrenergic synaptic transmission in the rat CNS. The effectiveness of the electrical stimulation of the locus coeruleus (LC) in suppressing the firing activity of pyramidal neurons was determined in the dorsal hippocampus. Intravenous clonidine, anα 2-adrenergic agonist, decreased the effectiveness of the LC stimulation without altering the effect of microiontophoretically applied norepinephrine. The subsequent i.v. administration of low doses of idazoxan, anα 2-adrenergic antagonist, reversed this effect of clonidine on the LC stimulation. To ascertain that the effect of clonidine administered i.v. was indeed attributable to its action on noradrenergic terminals, it was applied locally by microiontophoresis; it decreased the effectiveness of the LC stimulation. Another paradigm used to assess the function of terminalα 2-adrenoceptors was to increase the frequency of the LC stimulation from 1 to 5 Hz. This resulted in a 5-fold decrease of the effectiveness of the stimulation. That this was attributable to an enhanced activation of terminalα 2-adrenoceptors was suggested by the reversal of this effect of increasing the frequency of the LC stimulation by intravenous idazoxan. Furthermore, the degree of enhancement of the effectiveness of the LC stimulation by idazoxan was much greater at 5 than at 1 Hz. These results provide novel electrophysiological evidence for the potent regulatory role of terminalα 2-adrenoceptors on noradrenergic neurotransmission.