Biology subjects

Kolnier, D.

Publications and source records attributed to Kolnier, D..

2 recordsLinked to original sources

bioRxiv2024

Effects of ketamine and propofol on muscarinic plateau potentials in rat neocortical pyramidal cells

Propofol and ketamine are widely used general anaesthetics, but have different effects on consciousness: propofol gives a deeply unconscious state, with little or no dream reports, whereas vivid dreams are often reported after ketamine anaesthesia. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, while propofol is a {gamma}-aminobutyric-acid (GABAA) agonist, but these mechanisms do not fully explain how these drugs alter consciousness. Most previous in vitro studies of cellular mechanisms of anaesthetics have used brain slices or neurons in a nearly "comatose" state, because no "arousing" neuromodulators were added. Here we tested mechanisms of anaesthetics in slices after adding the cholinergic agonist muscarine to partly mimic an "awake-like" state. Using whole-cell patch-clamp recordings from layer 2/3 pyramidal cells (L2/3PCs) in rat medial prefrontal cortex (mPFC) slices, we saw that muscarine induced long-lasting depolarizing plateau potentials (PPs) and spiking following brief depolarizing current injections. According to leading theories of consciousness and working memory, L2/3PCs and PPs are particularly important for these cognitive functions. After 2 hours of pre-incubation with ketamine or propofol, the muscarine-induced PPs were altered in different ways: 3 {micro}M propofol reduced the PPs and (significantly) spiking, whereas 20 {micro}M ketamine seemed to enhance PPs and spiking (non-significantly). Brief wash-in of these drug concentrations failed to induce such effects, probably due to insufficient equilibration by diffusion in the slices. In contrast, pre-incubation with 100 {micro}M ketamine suppressed the PPs and spiking. The different effects on PPs may be related to contrasting clinical effects: ketamine causing atypical anaesthesia with vivid, "psychedelic" dreaming while propofol causes less dreaming. However, high ketamine or propofol concentrations both suppressed PPs, suggesting possible connections between PPs, desynchronized activity, and consciousness. More experiments are needed to test these tentative conclusions.

neuroscience↗

bioRxiv2023

Non-apical plateau potentials and persistent firing induced by metabotropic cholinergic modulation in layer 2/3 pyramidal cells in the rat prefrontal cortex

The prefrontal cortex (PFC) is important for executive functions, including attention, planning, decision-making, and memory, and is proposed by some leading theories to be crucial for consciousness. In particular, the global neuronal workspace theory proposes that PFC layer 2/3 pyramidal cells (L2/3PCs) contribute crucially to the global workspace, and hence to consciousness, due to their long-range connections to other cortical areas. Plateau potentials, periods of depolarisation with action potential firing outlasting the stimuli that induced them, have been suggested to help maintain working memory and to contribute to executive functions and consciousness. We therefore investigated plateau potentials and their mechanisms in PFC layer 2/3 pyramidal neurons. Using whole-cell somatic recordings from L2/3PCs in rat PFC brain slices, we found that the metabotropic cholinergic agonist muscarine reliably induced long-lasting plateau potentials with spiking following a train of evoked action potentials. Similar plateaus were induced by a metabotropic glutamate receptor (mGluR) agonist. Pharmacological tests suggested that these plateaus were dependent on transient receptor potential (TRP) cation channels, both TRPC4 and TRPC5, and required the presence of external calcium (Ca2+) and internal Ca2+ stores, but not voltage-gated Ca2+ channels. Using local Ca2+ applications, we found that the responsible Ca2+ influx is most likely distributed on the somatic and/or basal dendritic compartments rather than on the (distal) apical dendrite. We used knife cuts to disconnect apical dendrites, sometimes less than 50 {micro}m from the soma, and found that the plateaus did not depend on the distal apical dendrite, since truncated cells generated plateaus with as many spikes as control cells. These results indicate that layer 2/3PCs can generate plateau potentials with sustained spiking independently of distal apical dendrites.

neuroscience↗