Synapses are continually regulated by chemical modulators and by their own activity. We tested the specificity of regulation in two excitatory pathways of the neocortex: thalamocortical (TC) synapses, which mediate specific inputs, and intracortical (IC) synapses, which mediate the recombination of cortical information. Frequency-sensitive depression was much stronger in TC synapses than in IC synapses. The two synapse types were differentially sensitive to presynaptic neuromodulators: only IC synapses were suppressed by activation of GABA(B) receptors, only TC synapses were enhanced by nicotinic acetylcholine receptors, and muscarinic acetylcholine receptors suppressed both synapse types. Modulators also differentially altered the frequency sensitivity of the synapses. Our results suggest a mechanism by which the relative strength and dynamics of input and associational pathways of neocortex are regulated during changes in behavioral state.

Rhythmic activity in the neocortex varies with different behavioral and pathological states and in some cases may encode sensory information. However, the neural mechanisms of these oscillations are largely unknown. Many pyramidal neurons in layer 5 of the neocortex showed prolonged, 5- to 12-hertz rhythmic firing patterns at threshold. Rhythmic firing was due to intrinsic membrane properties, sodium conductances were essential for rhythmicity, and calcium-dependent conductances strongly modified rhythmicity. Isolated slices of neocortex generated epochs of 4- to 10-hertz synchronized activity when N-methyl-D-aspartate receptor-mediated channels were facilitated. Layer 5 was both necessary and sufficient to produce these synchronized oscillations. Thus, synaptic networks of intrinsically rhythmic neurons in layer 5 may generate or promote certain synchronized oscillations of the neocortex.

Thalamocortical (TC) synapses carry information into the neocortex, but they are far outnumbered by excitatory intracortical (IC) synapses. We measured the synaptic properties that determine the efficacy of TC and IC axons converging onto spiny neurons of layer 4 in the mouse somatosensory cortex. Quantal events from TC and IC synapses were indistinguishable. However, TC axons had, on average, about 3 times more release sites than IC axons, and the mean release probability at TC synapses was about 1.5 times higher than that at IC synapses. Differences of innervation ratio and release probability make the average TC connection several times more effective than the average IC connection, and may allow small numbers of TC axons to dominate the activity of cortical layer 4 cells during sensory inflow.

We studied the propagation of paroxysmal discharges in disinhibited neocortical slices by developing and analyzing a model of excitatory regular-spiking neocortical cells with spatially decaying synaptic efficacies and by field potential recording in rat slices. Evoked discharges may propagate both in the model and in the experiment. The model discharge propagates as a traveling pulse with constant velocity and shape. The discharge shape is determined by an interplay between the synaptic driving force and the neuron's intrinsic currents, in particular the slow potassium current. In the model, N-methyl-D-aspartate (NMDA) conductance contributes much less to the discharge velocity than amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) conductance. Blocking NMDA receptors experimentally with 2-amino-5-phosphonovaleric acid (APV) has no significant effect on the discharge velocity. In both model and experiments, propagation occurs for AMPA synaptic coupling gAMPA above a certain threshold, at which the velocity is finite (non-zero). The discharge velocity grows linearly with the gAMPA for gAMPA much above the threshold. In the experiments, blocking AMPA receptors gradually by increasing concentrations of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the perfusing solution results in a gradual reduction of the discharge velocity until propagation stops altogether, thus confirming the model prediction. When discharges are terminated in the model by the slow potassium current, a network with the same parameter set may display discharges with several forms, which have different velocities and numbers of spikes; initial conditions select the exhibited pattern. When the discharge is also terminated by strong synaptic depression, there is only one discharge form for a particular parameter set; the velocity grows continuously with increased synaptic conductances. No indication for more than one discharge velocity was observed experimentally. If the AMPA decay rate increases while the maximal excitatory postsynaptic conductance (EPSC) a cell receives is kept fixed, the velocity increases by approximately 20% until it reaches a saturated value. Therefore the discharge velocity is determined mainly by the cells' integration time of input EPSCs. We conclude, on the basis of both the experiments and the model, that the total amount of excitatory conductance a typical cell receives in a control slice exhibiting paroxysmal discharges is only approximately 5 times larger than the excitatory conductance needed for raising the potential of a resting cell above its action potential threshold.