Astrocytic mechanism for regulating dopaminergic burst firing

University Of Texas San Antonio, San Antonio TX

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Abstract

? DESCRIPTION (provided by applicant): Dopamine (DA) neurons located in the substantia nigra pars compacta and the ventral tegmental area generate signals involved in motivated behavior. DA neuron firing patterns encode different aspects of reward. Drugs of abuse, such as cocaine, usurp the dopaminergic system causing an increase in dopaminergic burst firing which increases dopamine release at target regions to levels unattainable by natural reward (e.g. eating, grooming, social interactions). Generation of burst firing involves activation of NMDA receptors (NMDARs); activation of NMDARs requires glutamate and glycine. Activation of AMPA receptors (AMPARs) and depolarization of astrocytes are known to release glycine in the substantia nigra. Thus, one mechanism that may regulate NMDAR activation is glycine release from astrocytes via AMPAR activation. The goal of this proposal is to study a novel mechanism for regulating burst firing of dopaminergic neurons by glycine release from midbrain astrocytes via activation of AMPARs. First, in vitro physiology will be used to determine if manipulating the extracellular concentration of glycine causes a change in burst firing. Burst firing will be evoked by electrical stimulation of glutamatergic afferents. Burst firing and NMDAR- mediated currents will be measured before and after pharmacologically increasing and decreasing the extracellular glycine concentration. Second, whether astrocytes can regulate DA neuron burst firing will be tested using optogenetics. This will be accomplished by optogenetic manipulation of astrocytic membrane potentials. Burst firing and NMDAR-mediated currents will be compared between electrical stimulation, and electrical stimulation paired with photoactivation of astrocytes. Lastl, whether AMPARs on astrocytes can modulate burst firing will be tested. This will be done by first measuring electrically evoked currents from astrocytes surrounding DA neurons before and after addition of a specific AMPAR blockers. Next, burst firing will be evoked by electrical stimulation, then AMPAR blockers will be added; burst and NMDAR-mediated currents will be compared between the two conditions. Next, in the presence of AMPAR blockers, electrical stimulation will be paired with photoactivation of astrocytes; burst and NMDAR-mediated currents will be compared. The proposal will grant a better understanding of the cellular mechanism that underlies burst firing in DA neurons.