NMDA Enhances and Glutamate Attenuates Synchrony of Spontaneous Phase-Locked Locus Coeruleus Network Rhythm in Newborn Rat Brain Slices

Abstract

Locus coeruleus (LC) neurons are controlled by glutamatergic inputs. Here, we studied in brain slices of neonatal rats NMDA and glutamate effects on phase-locked LC neuron spiking at ~1 Hz summating to ~0.2 s-lasting bell-shaped local field potential (LFP). NMDA: 10 μM accelerated LFP 1.7-fold, whereas 25 and 50 μM, respectively, increased its rate 3.2- and 4.6-fold while merging discrete events into 43 and 56% shorter oscillations. After 4–6 min, LFP oscillations stopped every 6 s for 1 s, resulting in ‘oscillation trains’. A dose of 32 μM depolarized neurons by 8.4 mV to cause 7.2-fold accelerated spiking at reduced jitter and enhanced synchrony with the LFP, as evident from cross-correlation. Glutamate: 25–50 μM made rhythm more irregular and the LFP pattern could transform into 2.7-fold longer-lasting multipeak discharge. In 100 μM, LFP amplitude and duration declined. In 25–50 μM, neurons depolarized by 5 mV to cause 3.7-fold acceleration of spiking that was less synchronized with LFP. Both agents: evoked ‘post-agonist depression’ of LFP that correlated with the amplitude and kinetics of Vm hyperpolarization. The findings show that accelerated spiking during NMDA and glutamate is associated with enhanced or attenuated LC synchrony, respectively, causing distinct LFP pattern transformations. Shaping of LC population discharge dynamics by ionotropic glutamate receptors potentially fine-tunes its influence on brain functions.

Mediation of Sinusoidal Network Oscillations in the Locus Coeruleus of Newborn Rat Slices by Pharmacologically Distinct AMPA and KA Receptors

“…Within 11.0 ± 4.0 min after the start of washout, the LFP recovered after depression or blockade. At intermediate AMPA doses that do not block the rhythm, recovery occurred with no arrest of discharge early during washout as seen in response to the bath-applied glutamate or N-methyl-D-aspartate in our recent study [ 1 ]. The original recordings already indicated that 0.25 and 0.5 µM AMPA made the LFP rate more regular.…”

“…We reported that LFP events in the LC of newborn rat slices are typically bell-shaped due to a normal distribution of single spikes whose sum jitters equally around the LFP peak [ 1 ]. Here, firstly dose-response relationships were determined for AMPA and KA effects.…”

“…The locus coeruleus (LC) in the lower brainstem controls many brain functions such as sleep, memory, anxiety, breathing, pain sensation, and opioid actions or addiction/withdrawal [ 1 , 2 , 3 , 4 ]. Specifically, the LC acts as a hub by releasing noradrenaline into most brain areas during its (tonic) spontaneous activity and, phasically, in response to afferent (sensory) synaptic inputs from various other brain circuits [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

“…As both these features and other in vivo limitations hamper pharmacological and electrophysiological analyses, particularly in newborns, brain slices are being used [ 22 , 23 , 24 , 25 ]. We recently showed in newborn rat slices that NMDAR activation transforms bell-shaped local field potential (LFP) events that are occurring at 1 Hz into faster burst-like multipeak signals [ 1 ]. Also AMPARs seem to be functional in the newborn rat LC as indicated by our finding [ 27 ] that CNQX may act here as a partial agonist due to their coupling to transmembrane AMPAR proteins (TARP) [ 28 , 29 ].…”

“…Also AMPARs seem to be functional in the newborn rat LC as indicated by our finding [ 27 ] that CNQX may act here as a partial agonist due to their coupling to transmembrane AMPAR proteins (TARP) [ 28 , 29 ]. It was the aim of the present study to use the same in vitro approaches as in our latter report [ 1 ] to investigate whether AMPARs and KARs are both functional, have different pharmacological properties and may thus have distinct effects on the neonatal LC network. Such information will enhance the understanding of mechanistic neonatal LC network organization to study in the future, e.g., whether (one of) these iGluR sub-types contributes to the in vivo-like opioid-evoked slow bursting that we found in newborn rat slices [ 30 , 31 ].…”