Activation of 5-HT_2Areceptors by TCB-2 induces recurrent oscillatory burst discharge in layer 5 pyramidal neurons of the mPFC in vitro

Abstract

The medial prefrontal cortex (mPFC) is a region of neocortex that plays an integral role in several cognitive processes which are abnormal in schizophrenic patients. As with other cortical regions, large‐bodied layer 5 pyramidal neurons serve as the principle subcortical output of microcircuits of the mPFC. The coexpression of both inhibitory serotonin 5‐HT1A receptors on the axon initial segments, and excitatory 5‐HT2A receptors throughout the somatodendritic compartments, by layer 5 pyramidal neurons allows serotonin to provide potent top–down regulation of input–output relationships within cortical microcircuits. Application of 5‐HT2A agonists has previously been shown to enhance synaptic input to layer 5 pyramidal neurons, as well as increase the gain in neuronal firing rate in response to increasing depolarizing current steps. Using whole‐cell patch‐clamp recordings obtained from layer 5 pyramidal neurons of the mPFC of C57/bl6 mice, the aim of our present study was to investigate the modulation of long‐term spike trains by the selective 5‐HT2A agonist TCB‐2. We found that in the presence of synaptic blockers, TCB‐2 induced recurrent oscillatory bursting (ROB) after 15–20 sec of tonic spiking in 7 of the 14 cells. In those seven cells, ROB discharge was accurately predicted by the presence of a voltage sag in response to a hyperpolarizing current injection. This effect was reversed by 5–10 min of drug washout and ROB discharge was inhibited by both synaptic activity and coapplication of the 5‐HT2A/2C antagonist ketanserin. While the full implications of this work are not yet understood, it may provide important insight into serotonergic modulation of cortical networks.

Dopaminergic D1 receptor effects on commissural inputs targeting layer V pyramidal subtypes of the mouse medial prefrontal cortex

“…A total of nine animals were used in the study and a total of 17 cells were recorded (PT: n = 9; IT: n = 8). As demonstrated in previous studies (Dembrow et al, ; Gee et al, ; Spindle and Thomas, ; Leyrer‐Jackson and Thomas, ), layer V pyramidal cell subtypes identified by retrobead labeling displayed differences in their electrophysiological properties. Although the two cell types differed in some characteristics, they did not differ in membrane capacitance (PT: 135.2 ± 19.3 pF; IT: 149.9 ± 12.9 pF; P > 0.05), resting membrane potential (PT: −65.7 ± 1.6 mV; IT: −65.6 ± 2.0 mV; P > 0.05), or membrane resistance (PT: 107.2 ± 14.2 Mohm; IT: 135.6 ± 25.5 Mohm; P > 0.05) (Fig.…”

“…PT cells also typically fired initial doublets in response to depolarizing current injections, which was never observed in IT cells. Both of these criteria have been used in previous studies to identify layer V subtypes (Dembrow et al, 2010;Gee et al, 2012;Lee et al, 2014;Spindle and Thomas, 2014).…”

Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures

“…Nevertheless, one might speculate that the putative 5-HT 2A R-dependent i) decrease in firing of pyramidal cells in vivo ( Ashby et al., 1990 ), ii) increase in IPSCs in vitro in pyramidal cells ( Zhou and Hablitz, 1999 ) and iii) depolarization of fast-spiking interneurons in vitro (Weber and Andrade, 2010) may all be contributing to a reduced firing activity in the putative cortical “initiation site” from where SWDs firstly originate ( Polack et al., 2007 ), thus explaining the reduction of ASs observed in the present study following 5-HT 2A R activation. However, it should be noted that the putative 5-HT 2A R-dependent increase in firing rate ( Zhang and Arsenault, 2005 ) and burst discharges which have been reported in layer 5 pyramidal neurons in vivo ( Celada et al., 2008 , Spindle and Thomas, 2014 ) could be favoring, and not reducing, AS expression. At the thalamic level, 5-HT and putative 5-HT 2C R agonists depolarize TC neurons ( Chapin and Andrade, 2001 , Meuth et al., 2006 , Pape and McCormick, 1989 ).…”

“…However we note that the available data on vigilance state alterations elicited by 5-HT 2A R and 5-HT 2C R activation are contradictory. 5-HT 2A R and 5-HT 2C R KO mice show increased waking and reduced non-REM sleep ( Spindle and Thomas, 2014 ). On the other hand, systemic administration of DOI ( Monti and Jantos, 2006 ) and RO60-0175 ( Martin et al., 1998 , Monti and Jantos, 2015 ) increases waking and reduces non-(rapid eye movement) REM and REM sleep.…”

Layer-specific effects of dopaminergic D1 receptor activation on excitatory synaptic trains in layer V mouse prefrontal cortical pyramidal cells

“…Type I and type II layer V pyramidal cells were identified based on the presence of a prominent “sag” in response to a 150 pA hyperpolarizing current (type I: minimal 12% depolarization from peak of hyperpolarization, indicating the strong presence of the hyperpolarization activated cation current), and by initial firing of doublets (type I cells only); both criteria have been used in previous studies (Dembrow et al. ; Spindle and Thomas ). For all analyses, type I and type II subtypes were categorized and compared between experimental groups.…”