GABAERGIC MODULATION OF HIPPOCAMPAL POPULATION ACTIVITY - SEQUENCE LEARNING, PLACE FIELD DEVELOPMENT, AND THE PHASE PRECESSION EFFECT

A detailed biophysical model of hippocampal region CA3 was constructed to study how GABAergic modulation influences place field development and the learning and recall of sequence information. Simulations inclu ded 1,000 multicompartmental pyramidal cells, each consisting of seven intrinsic and four synaptic currents, and 200 multicompartmental inte rneurons, consisting of two intrinsic and four synaptic currents. Exci tatory rhythmic septal input to the apical dendrites of pyramidal cell s and both excitatory and inhibitory input to interneurons at theta fr equencies provided a cellular basis for the development of theta and g amma frequency oscillations in population activity. The fundamental fr equency of theta oscillations was dictated by the driving rhythm from the septum. Gamma oscillation frequency, however, was determined by bo th the decay time of the gamma-aminobutyric acid-A (GABA(A))-receptor- mediated synaptic current and the overall level of excitability in int erneurons due to alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid and N-methyl-D-aspartate (NMDA)-receptor-gated channel activatio n. During theta population activity, total GABAB-receptor-mediated con ductance levels were found to gradually rise and fall in rhythmic fash ion with the predominant population frequency (theta rhythm). This res ulted in periodic GABA(B)-receptor-mediated suppression of excitatory synaptic transmission at recurrent collaterals (intrinsic fibers) of p yramidal cells and suppression of inhibitory synaptic transmission to both pyramidal cells and interneurons. To test the ability of the mode l to learn and recall temporal sequence information, a completion task was employed. During learning, the network was presented a sequence o f nonorthogonal spatial patterns. Each input pattern represented a spa tial ''location'' of a simulated rat running a specific navigational p ath. Hebbian-type learning was expressed as an increase in postsynapti c NMDA-receptor-mediated conductances. Because of several factors incl uding the sparse, asymmetric excitatory synaptic connections among pyr amidal cells in the model and a sufficient degree of random ''backgrou nd'' firing unrelated to the input patterns, repeated simulated runs r esulted in the gradual emergence of place fields where a given cell be gan to respond to a contiguous segment of locations on the path. Durin g recall, the simulated rat was placed at a random location on the pre viously learned path and tested to see whether the sequence of locatio ns could be completed on the basis of this initial position. Periodic GABA(B)-receptor-mediated suppression of excitatory and inhibitory tra nsmission at intrinsic but not afferent fibers resulted in sensory inf ormation about location being dominant during early portions of each t heta cycle when GABA(B)-receptor-related effects were highest. This su ppression declined with levels of GABA(B) receptor activation toward t he end of a theta cycle, resulting in an increase in synaptic transmis sion at intrinsic fibers and the subsequent recall of a segment of the entire location sequence. This scenario typically continued across th eta cycles until the full sequence was recalled. When the GABA(B)-rece ptor-mediated suppression of excitatory and inhibitory transmission at intrinsic fibers was not included in the model, place field developme nt was curtailed and the network consequently exhibited poor learning and recall performance. This was, in part, due to increased competitio n of information from intrinsic and afferent fibers during early porti ons of each theta cycle. Because afferent sensory information did not dominate early in each cycle, the current location of the rat was obsc ured by ongoing activity from intrinsic sources. Furthermore, even whe n the current location was accurately identified, competition between afferent and intrinsic sources resulted in a tendency for rapid recall of several locations at once, which often lead to inaccuracies in the sequence. Thus the rat often recalled a path different from the parti cular one that was learned. GABA(B)-receptor-mediated modulation of ex citatory synaptic transmission within a theta cycle resulted in a syst ematic relationship between single-unit activity and peaks in pyramida l cell population behavior (theta rhythm). Because presynaptic inhibit ion of intrinsic fibers was strongest at early portions of each theta cycle, single-unit firing usually started late in a cycle as the place field of the associated cell was approached. This firing typically ad vanced to progressively earlier phases in a theta cycle as the place f ield was traversed. Thus, as the rat moved through successive location s along a learned trajectory during completion trials, place cell firi ng gradually shifted from late phases of a theta cycle, where future l ocations were ''predicted'' (intrinsic information dominated), to earl y phases of a cycle, where the current location was ''perceived'' (aff erent sources dominated). This result suggests that the GABAergic modu lation of temporal sequence learning may serve as a general framework for understanding navigational phenomena such as the phase precession effect.