TEMPORAL COVARIANCE OF PRESYNAPTIC AND POSTSYNAPTIC ACTIVITY REGULATES FUNCTIONAL CONNECTIVITY IN THE VISUAL-CORTEX

It has been suggested from mathematical models and in vivo experiments in the visual cortex that periods of temporal covariance of pre- and postsynaptic activity can lead to a potentiation or depression of syna ptic efficacy. We directly tested this hypothesis in vitro in the guin ea pig and cat visual cortex. Intracellular recordings were made in br ain slices from 63 neurons in layers 2-4 in bicuculline-free artificia l cerebrospinal fluid. Twenty-nine cells (n = 25 from pigmented guinea pigs and 4 from cats) were taken through a complete series of control and test protocols to evaluate the covariance hypothesis. Some (n = 7 ) cells that were taken through the complete experimental protocols we re also filled intracellularly with biocytin. Compound postsynaptic po tentials (PSPs) were evoked by low-frequency (0.2-1.0 Hz), weak (20% o f threshold intensity) stimulation of the cortical white matter and/or intracortical sites in layers 2-3. In one series of experiments we pa ired PSPs with imposed coincident depolarizing (S+) or hyperpolarizing (S-) pulses (mean +/- 2.8 nA for 50-80 ms) of the postsynaptic neuron (n = 54 PSPs; >1 pairing protocol was often run on an individual cell) . Controls consisted of analyzing the same number of S+ or S- pairings but with long temporal delays called fixed delay pairings (FDPs) be tween the test pathway stimulation and the onset of the intracellular current pulse ( 120 ms) and pseudopairings (PP) consisting of evoked P SPs and delivery of intracellular current injection pulses in a phase- independent manner. Twenty-one of 54 PSPs subjected to pairing were si gnificantly modified by the protocol. The S+ protocol significantly (P < 0.05, Kolmogorov-Smirnov test) increased the peak amplitudes of 8 o f 22 PSPs (+20 to +55%); the S- protocol significantly decreased the p eak amplitudes of 13 of 32 PSPs (-15 to -88%), whereas the FDP and PP protocols generally did not cause significant changes in the PSPs (0% and 4%, respectively). Significant changes in PSPs persisted in most c ases for 10-20 min. Another series of experiments consisted of evaluat ing for the same cell the effects of evoking a PSP from one stimulatio n site without concomitant postsynaptic activation and alternately evo king a PSP from the other stimulation site with S+ or S- pairing (n = 25 PSPs). Only the paired pathway showed the predicted effects on the PSP (S+ pairing causing an increase in peak PSP amplitude and S- pairi ng causing a decrease in peak PSP amplitude). In no cases (0 of 25) di d the unpaired pathway show a similar effect. However, in 8 of those 2 5 cases the PSP of the unpaired pathway was significantly affected but the effect was opposite in polarity to that of the paired pathway PSP . The specificity of the S+ and S- effects was demonstrated not only b y a lack of generalization to other synaptic pathways to the same cell but also by lack of effect of the pairing protocols on the cells' res ting membrane potential, input resistance, or spike generating thresho ld. 6. Our results support the hypothesis that the ''effective'' stren gth of a functional pathway can be reversibly up- and down-regulated i n a temporally and spatially specific manner, depending on the sign an d amplitude of the temporal correlation between local postsynaptic mem brane polarization and change in afferent activity. This is consistent with the covariance hypothesis and a number of observations of dynami c modulation of effective connectivity in the cerebral cortex.