Alfaxalone Causes Reduction of Glycinergic IPSCs, but Not Glutamatergic EPSCs, and Activates a Depolarizing Current in Rat Hypoglossal Motor Neurons

Abstract

We investigated effects of the neuroactive steroid anesthetic alfaxalone on intrinsic excitability, and on inhibitory and excitatory synaptic transmission to hypoglossal motor neurons (HMNs). Whole cell recordings were made from HMNs in brainstem slices from 7 to 14-day-old Wistar rats. Spontaneous, miniature, and evoked inhibitory post-synaptic currents (IPSCs), and spontaneous and evoked excitatory PSCs (EPSCs) were recorded at –60 mV. Alfaxalone did not alter spontaneous glycinergic IPSC peak amplitude, rise-time or half-width up to 10 μM, but reduced IPSC frequency from 3 μM. Evoked IPSC amplitude was reduced from 30 nM. Evoked IPSC rise-time was prolonged and evoked IPSC decay time was increased only by 10 μM alfaxalone. Alfaxalone also decreased evoked IPSC paired pulse ratio (PPR). Spontaneous glutamatergic EPSC amplitude and frequency were not altered by alfaxalone, and evoked EPSC amplitude and PPR was also unchanged. Alfaxalone did not alter HMN repetitive firing or action potential amplitude. Baseline holding current at −60 mV with a CsCl-based pipette solution was increased in an inward direction; this effect was not seen when tetrodotoxin (TTX) was present. These results suggest that alfaxalone modulates glycine receptors (GlyRs), causing a delayed and prolonged channel opening, as well as causing presynaptic reduction of glycine release, and activates a membrane current, which remains to be identified. Alfaxalone selectively reduces glycinergic inhibitory transmission to rat HMNs via a combination of pre- and post-synaptic mechanisms. The net effect of these responses to alfaxalone is to increase HMN excitability and may therefore underlie neuro-motor excitation during neurosteroid anesthesia.

Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression

“…Several recent studies show that in the adult, there are indications that ethanol could have positive effects particularly for the traumatized brain [ 3 – 10 , 50 ]. Some of the mechanisms proposed to mediate this positive effect of low concentrations of ethanol are to suppress apoptosis and inflammation.…”

“…Strikingly, these studies found a strong correlation between low intake and lower risk and severity of post-ischemic injury. Both effects in apoptosis and inflammation are proposed to be involved in the mechanism in rodents [ 9 , 10 ].…”

Alfaxalone for total intravenous anaesthesia in horses

“…We hypothesised that the central nervous effects may be linked to synaptic plasticity and neuromodulation at the GABA A and glycine receptor. Lau et al (2010) reported that in an in vitro hypoglossal nerve model, alfaxalone reduces glycinergic inhibitory transmission which made the nerve more "accessible" to…”

Inhibitory Synaptic Influences on Developmental Motor Disorders

“…Glycinergic inhibitory synaptic transmission is prevalent in the brainstem and spinal cord [ 17 , 21 , 22 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ], although some other brain areas also demonstrate functional glycinergic transmission [ 90 ]. The ionotropic actions of glycinergic neurotransmission are mediated by the glycine receptor ( Figure 2 ) and plays an important role in modulating motor patterns and motor circuit interneurons and MNs [ 90 , 99 , 100 , 101 ].…”

“…Despite the cortical and pattern-generator (brainstem or spinal segment) influence on motor unit activation and the interactions of cerebellar and striatal regions on motor output, the MN is eminently capable of neural computation [ 12 , 13 ]. Indeed, the MN is the final common pathway, and receive excitatory (predominantly glutamatergic) inputs and both GABAergic and/or glycinergic inhibitory inputs, amongst a host of other extrinsic and intrinsic excitability modulators [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. A simplified summary of neuromotor control shows key differences between respiratory and locomotor circuits ( Figure 1 ), with respiratory circuits governed by a centralized pattern/rhythm generator (the pre-Bötzinger complex) [ 10 , 31 ] and locomotor circuits with distributed pattern generation at various segments of the brainstem and spinal cord [ 32 , 33 , 34 , 35 ].…”