Neocortical pyramidal neurons express several distinct subtypes of voltage-gated Na channels. In mature cells, Na1.6 is the dominant channel subtype in the axon initial segment (AIS) as well as in the nodes of Ranvier. Action potentials (APs) are initiated in the AIS, and it has been proposed that the high excitability of this region is related to the unique characteristics of the Na1.6 channel. Knockout or loss-of-function mutation of the gene is generally lethal early in life because of the importance of this subtype in noncortical regions of the nervous system. Using the Cre/loxP system, we selectively deleted Na1.6 in excitatory neurons of the forebrain and characterized the excitability of Na1.6-deficient layer 5 pyramidal neurons by patch-clamp and Na and Ca imaging recordings. We now report that, in the absence of Na1.6 expression, the AIS is occupied by Na1.2 channels. However, APs are generated in the AIS, and differences in AP propagation to soma and dendrites are minimal. Moreover, the channels that are expressed in the AIS still show a clear hyperpolarizing shift in voltage dependence of activation, compared with somatic channels. The only major difference between Na1.6-null and wild-type neurons was a strong reduction in persistent sodium current. We propose that the molecular environment of the AIS confers properties on whatever Na channel subtype is present and that some other benefit must be conferred by the selective axonal presence of the Na1.6 channel.

Because the excitable properties of neurons in the neocortex depend on the characteristics of voltage-gated Na ؉ channels, factors which regulate those characteristics can fundamentally modify the dynamics of cortical circuits. Here, we report on a novel neuromodulatory mechanism that links the availability of Na ؉ channels to metabolism of polyamines (PAs) in the cerebral cortex. Using single channel and whole-cell recordings, we found that products of PA metabolism, the ubiquitous aliphatic polycations spermine and spermidine, are endogenous blockers of Na ؉ channels in layer 5 pyramidal cells. Because the blockade is activity-dependent, it is particularly effective against Na ؉ channels which fail to inactivate rapidly and thus underlie the persistent Na ؉ current. At the level of the local cortical circuit, pharmacological depletion of PAs led to increased spontaneous spiking and periods of hypersynchronous discharge. Our data suggest that changes in PA levels, whether associated with normal brain states or pathological conditions, profoundly modify Na ؉ channel availability and thereby shape the integrative behavior of single neurons and neocortical circuits.neocortex ͉ Layer 5 pyramidal neuron ͉ persistent sodium current ͉ sodium channel ͉ spermine