Modulation of synaptic transmission by coactivation of presynaptic GABAA and GABAB receptors: kinetics, plasticity, and functional consequences

通过共激活突触前 GABAA 和 GABAB 受体来调节突触传递：动力学、可塑性和功能后果

• 批准号: 9321172
• 负责人: Jason Richard Pugh
• 金额: $ 33.04万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321172
• 关键词: Address; Affinity; Autistic Disorder; Axon; Calcium; Cells; Cerebellum; Dependence; Development; Electrophysiology (science); Epilepsy; Equilibrium; Etiology; Excitatory Synapse; Fiber; Foundations; Frequencies; Future; GABA Receptor; Glutamates; Goals; Image; Information Storage; Investigation; Kinetics; Laser Scanning Microscopy; Learning; Ligands; Long-Term Potentiation; Membrane; Mental Depression; Neuraxis; Neurologic; Neurotransmitters; Physiology; Plasticizers; Presynaptic Receptors; Probability; Process; Property; Receptor Activation; Regulation; Schizophrenia; Synapses; Synaptic Transmission; Synaptic plasticity; System; Time; Training; Work; base; experience; gamma-Aminobutyric Acid; granule cell; in vivo; neuronal circuitry; neurotransmission; novel; patch clamp; postsynaptic; postsynaptic neurons; presynaptic; public health relevance; receptor; receptor expression; receptor function; response; transmission process; two-photon; vesicular release

 DESCRIPTION (provided by applicant): The long term goal of this project is to understand how presynaptic receptors, specifically GABAA and GABAB receptors, influence synaptic transmission, cellular computation, and learning in neuronal circuits. GABAA and GABAB receptors are co-expressed in the presynaptic membrane of many excitatory synapses in the central nervous system where they have been shown to modulate synaptic transmission. However, previous studies have generally studied the effects of each receptor type in isolation and with static conditions. It is not currently known how co-activation of these receptors, as is likely to happen in vivo, will modulate synaptic transmission. We propose that expression of presynaptic GABA receptors is a plastic property of the synapse and presynaptic GABA receptors function together to temporally modulate synaptic transmission. Previous work has shown that axons of cerebellar granule cells express both presynaptic GABAA and GABAB receptors, which increase and decrease, respectively, glutamate release at parallel fiber synapses (Dittman and Regehr, 1996; Stell et al., 2007; Pugh and Jahr, 2011; Dellal et al., 2012). Using a combination of whole-cell patch clamp electrophysiology and two-photon laser scanning microscopy (including calcium imaging), this project will demonstrate that, rather than opposing one another, presynaptic GABAA and GABAB receptors function together to temporally modulate transmission and enhance short-term plasticity, a result not possible from activation of either receptor alone. Furthermore, this work will show that expression of presynaptic GABA receptors is regulated by long-term changes in synaptic strength. This work will reveal novel forms of synaptic plasticity and presynaptic receptor function. Regulation of excitatory transmission by presynaptic GABA receptors may be a general mechanism of balancing excitation and inhibition in the central nervous system and disruption of this system may contribute to the etiology and treatment of neurological conditions associated with synaptic imbalances, such as autism, schizophrenia and epilepsy. Aim 1: Determine the effects of GABAA and GABAB receptor co-activation on vesicle release. Hypothesis: Rather than opposing one another, differences in kinetics and affinity of GABAA and GABAB receptors allow them to work together to produce a biphasic effect on release probability. Aim 2: Determine the conditions for presynaptic GABAA and GABAB receptor plasticity. Hypothesis: Presynaptic GABAA and GABAB receptor expression is modulated in opposition to long-term changes in synapse strength. Aim 3: Determine the effects of presynaptic GABAA and GABAB receptors on postsynaptic firing and associative (postsynaptic) plasticity. Hypothesis: Activation of presynaptic GABA receptors enhances short-term facilitation and depression during trains of high frequency-activity, narrowing the duration of postsynaptic firing and the window for long-term plasticity at parallel fiber synapses. Relevance: A precise balance of excitation and inhibition is required for proper functioning of neuronal circuits while imbalances have been associated with several neurological conditions, including autism, schizophrenia, and epilepsy. This work will determine how neurotransmission at excitatory synapses is regulated by the inhibitory neurotransmitter, GABA. This work will lay the groundwork of basic synaptic physiology for future studies investigating dysregulation of excitation and inhibition in these conditions.