Recipient Organization
IOWA STATE UNIVERSITY
S. AND 16TH ELWOOD
AMES,IA 50011
Performing Department
VETERINARY MEDICINE
Non Technical Summary
How information transmission through GABA B receptors is modulated by neural activity, and how such activity-dependent synaptic modulation may function in regulating brain activity are largely unknown. The goal of this project is clarify how synaptic transmission through GABA B receptors is modulated by pre- and postsynaptic activity and how this synaptic modulatin affects the generation of the sleep rhythm in thalamic networks.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
The regulation of neural activity by GABAergic synapses is essential for the brain to process sensory information accurately as well as to generate adaptive behaviors. The disruption of GABAergic synapses not only interrupts those basic brain functions but also leads to the abnormal discharges that underlie various forms of brain disorders. Such regulatory GABAergic functions are implemeted through activation of two major types of receptors, GABA A and GABA B, in most parts of the brain. In spite of working through only two types of receptors, GABAergic synapses are highly effective in their regulation of brain activity. This effective regulation arises, at least in part, from the ability of GABAergic synapses to modulate their own transmission through GABA A receptors in an activity-dependent manner. In contrast, how information transmission through GABA B receptors is modulated by neural activity, and how such activity-dependent synaptic modulation may function in
regulating brain activity are largely unknown. The primary goal of this project is to elucidate how synaptic transmission through GABA B receptors is modulated by pre- and postsynsaptic activity, and how this synaptic modulation affects the generation of the sleep rhythm in thalamic networks. To answer this, four questions need to be answered: 1) How is synaptic transmission through GABA B receptors modified by presynaptic activity? 2) Does the fast activation of GABA A receptors regulate down the slow GABA B receptor-mediated response through activation of a hyperpolarization-activiated cation current (Ih)? 3) How are multiple GABAergic inputs summated through GABA B receptors? and 4) Does an increase in the activation of GABA B receptors by a dysfunctional GABA uptake system alter the sleep spindle rhythm into generalized epilepsy?
Project Methods
To achieve our primary goal we will generate brain slices from the dorsal lateral geniculate nucleus (LGNd) of the thalamus. Recently, by using dual intracellular recordings from monosynaptically connected pairs of cells in the thalmus, we demonstrated that activation of a single GABAergic cell can activate both GABA A and GABA B receptors in the postsynaptic cell. In this model system with dual recordings, the concomitant activation of both GABA A and GABA B receptors by a single GABAergic cell, as well as the rigorous control and accurate monitoring of pre- and postsynaptic activity, offer an effective approach for exploring the details of synaptic transmission through GABA B receptors. Using the same dual recording arrangements, we will examine the plasticity of GABAergic tranmission through GABA B receptors, and whether synpatic efficacy changes as the presynaptic cell varies in pattern of action potentials. We will also determine whether activation of GABA A
receptors indeed shunts down GABA B receptor-mediated responses through activation of Ih. Also, we will examine and compare the arithmetic by which multiple GABAergic inputs are summated through GABA A - and GABA B receptors. Finally, we will examine how the blockage of the GABA uptake system in the thalamus shift the balance in the transmission through GABA A- and GABA B receptors, and whether a reduction in the efficiency in GABA uptake can alter the sleep spindle rhythm into 3 Hz absence epilepsy by increasing transmission through GABA B receptors.