Astrocytic involvement in cortical inhibition and serotonin neuromodulation
Quon, Liz 1991-
A single astrocyte can ensheath more than 100,000 synapses within its domain. Thus, astrocytes are ideally positioned to integrate signals from a few synapses to have impact on all ensheathed synapses with high efficiency. As neuromodulators are released in a volume manner and are known to illicit astrocyte calcium responses, we hypothesized that astrocytes may be effector cells, extending neuromodulator action to every synapse. Using live mouse brain slices, extracellular recordings of evoked excitatory postsynaptic potentials (eEPSPs), and select pharmacology, we assessed the astrocytic involvement in paired-pulse suppression and serotonin-mediated shaping of a simple sensory cortical network containing both excitatory and inhibitory activity. Using a paired-pulse stimulus repeated every 20 seconds, we assessed the role of astrocytes in paired-pulse suppression by applying pharmacological agents in the bath perfusate to interfere with astrocyte function. We then applied them in the presence of the GABAA antagonist bicuculline to determine if effects were dependent on GABA. To assess the role of astrocytes in serotonin neuromodulation, serotonin was administered as a bolus to the bath perfusate upstream of the recording site to simulate transient effects on the network. Serotonin was applied both before and after bath application of pharmacological agents considered to affect astrocyte function or signaling mechanisms. In the absence of neuromodulators or pharmacological agents, the first cortical eEPSP is much larger in amplitude than the second due to the recruitment of longer-lasting inhibitory activity resulting from the first stimulus. Pharmacological disruption of 1) astrocytic mGluR5 receptors, 2) astrocyte metabolism, 3) gap junctions/hemichannels, or 4) purinergic receptors resulted in a significant loss of this evoked inhibition in field recordings, suggesting that astrocytes may play a role in tonic aspects of network inhibition. Furthermore, all significance was lost when performed in the presence of bicuculline, suggesting that astrocytic involvement in paired-pulse suppression is GABAA dependent. In addition to effects seen on tonic cortical inhibition, serotonin effects on frequency transmission in the cortical network are significantly altered following pharmacological astrocyte disruption. Lastly, serotonin-mediated frequency transmission could also be disrupted using P2 antagonists suggesting that ATP signaling (astrocyte currency) may be involved. These data highlight a potential role for astrocytes in cortical inhibitory activity seen in this sensory cortical network and that serotonin acts on astrocytes to partially exert its modulatory influence.
DegreeMaster of Science (M.Sc.)
SupervisorBekar, Lane K
CommitteeGopalakrishnan, Venkat; Taghibiglou, Changiz; Walz, Wolfgang
Copyright DateOctober 2016