REGULATION OF THE NMDA COMPONENT OF EPSPS BY DIFFERENT COMPONENTS OF POSTSYNAPTIC GABAERGIC INHIBITION - COMPUTER-SIMULATION ANALYSIS IN PIRIFORM CORTEX

Physiological analysis in the companion paper demonstrated that gamma- aminobutyric acid-A (GABA(A))-mediated inhibition in piriform cortex i s generated by circuits that are largely independent in apical dendrit ic and somatic regions of pyramidal cells and that GABA(A)-mediated in hibitory postsynaptic currents (IPSCs) in distal dendrites have a slow er time course than those in the somatic region. This study used model ing methods to explore these characteristics of GABA(A)-mediated inhib ition with respect to regulation of the N-methyl-D-aspartate (NMDA) co mponent of excitatory postsynaptic potentials. Such regulation is rele vant to understanding NMDA-dependent long-term potentiation (LTP) and the integration of repetitive synaptic inputs that can activate the NM DA component as well as pathological processes that can be activated b y overexpression of the NMDA component. A working hypothesis was that the independence and differing properties of IPSCs in apical dendritic and somatic regions provide a means whereby the NMDA component and ot her dendritic processes can be controlled by way of GABAergic tone wit hout substantially altering system excitability. The analysis was perf ormed on a branched compartmental model of a pyramidal cell in pirifor m cortex constructed with physiological and anatomic data derived by w hole cell patch recording. Simulations with the model revealed that NM DA expression is more effectively blocked by the slow GABA(A) componen t than the fast. Because the slow component is present in greater prop ortion in apical dendritic than somatic regions, this characteristic w ould increase the capacity of dendritic IPSCs to regulate NMDA-mediate d processes. The simulations further revealed that somatic-region GABA ergic inhibition can regulate the generation of action potentials with Little effect on the NMDA component generated by afferent fibers in a pical dendrites. As a result, if expression of the NMDA component or o ther dendritic processes were enabled by selective block of dendritic inhibition, for example, by centrifugal fiber systems that may regulat e learning and memory, the somatic-region IPSC could preserve system s tability through feedback regulation of firing without counteracting t he effect of the dendritic-region block. Simulations with paired input s revealed that the dendritic GABA(A)-mediated IPSC can regulate the e xtent to which a strong excitatory input facilitates the NMDA componen t of a concurrent weak input, providing a possible mechanism for contr ol of ''associative LTP'' that has been demonstrated in this system. P ostsynaptic GABA(B)-mediated inhibition had less effect on the NMDA co mponent than either the fast or slow GABA(A) components. Depolarizatio n from a concomitant lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropioni c acid (AMPA) component also was found to have comparatively little ef fect on current through the NMDA channel because of its brief time cou rse.