Pei ZhangFollow

Date of Completion

5-3-2016

Embargo Period

10-30-2016

Keywords

Neuroscience, Adenosine, Neocortex, Neuromodulation, Exitation, Inhibition

Major Advisor

Maxim Volgushev

Associate Advisor

Joseph Loturco

Associate Advisor

Daniel Mulkey

Associate Advisor

Andrew Moiseff

Associate Advisor

Randall Walikonis

Field of Study

Physiology and Neurobiology

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Adenosine is a widespread neuromodulator in the brain performing a wide range of physiological and pathological functions of neurons and glia cells. Despite a wealth of researches on adenosine affects in many brain areas, operation of neurons and networks by adenosine in the neocortex is poorly understood, mostly because modulation of inhibitory transmission and excitation-inhibition balance by adenosine has been understudied. To clarify adenosine’s role at inhibitory synapses, and in excitation–inhibition balance in pyramidal neurons, we recorded pharmacologically isolated inhibitory responses, compound excitatory–inhibitory responses and spontaneous events in layer 2/3 and layer 5 pyramidal neurons in slices from rat visual cortex. We show that adenosine suppresses inhibitory transmission to these neurons in a concentration-dependent and reversible manner. The suppression was mediated by presynaptic A1 receptors (A1Rs) and associated with changes of presynaptic release probability indicated by paired pulse ratio (PPR) and coefficient variance (CV). At a portion of synapses of layer 2/3 we found evidence for A2ARs: their blockade led to a small but significant increase of the magnitude of adenosine-mediated suppression. This effect may be an indirect modulation the A1R-mediated suppression. At both excitatory and inhibitory synapses, the magnitude of A1R-mediated suppression and A2AR–A1R interaction expressed high variability, suggesting high heterogeneity of synapses in the sensitivity to adenosine. In layer 5, overall A2AR-mediated effects seem to be weaker but heterogeneity of individually modulated synapses still exists. Adenosine could change the balance between excitation and inhibition at

set of inputs to a neuron bidirectionally, towards excitation or towards inhibition. In layer 2/3, the overall balance of excitation and inhibition was maintained during application of adenosine whereas in layer 5 the excitation-inhibition balance was significantly shifted towards inhibition. These results suggest that changes of adenosine concentration may lead to differential modulation of excitatory–inhibitory balance in pyramidal neurons of different layers, and thus redistribution of local spotlights of activity in neocortical circuits, while preserving the balanced state of the whole network.

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