Rationale:
Slow frequency oscillations in neocortical activity are often accompanied by loss of consciousness during natural sleep and anesthesia. Pathological slow rhythms in the form of ictal neocortical slow waves also occur with some types of epilepsy. The cellular mechanisms responsible for amplifying these slow oscillations remain elusive, but classic work in rodent implicates layer 5 (L5) excitatory pyramidal neurons (PNs) that exhibit a low threshold for initiating epileptiform bursts. To bridge this gap, we explored two cellular mechanisms by which the extratelencephalic-projecting (L5 ET) subset of PNs may contribute to amplification of slow oscillations. First, we have previously shown that mouse L5 ET PNs basal dendrites respond to stimuli mimicking desynchronized network activity with all-or-none NMDA-spikes, whereas in the intratelencephalic PNs respond in a more graded manner. Here we tested how stimulus patterns mimicking network oscillations are integrated, and whether such properties are also observed in primate neurons. A second mechanism by which L5 ET PNs regulate the propagation of low frequency oscillations in healthy neocortex is by suppressing repetitive burst firing in response to tonic input with Kv2.1 ion channels. Loss of function mutations in either Kv2 channels or their auxiliary subunits have been identified as causes of epilepsy in humans. In mouse, L5 ET neurons preferentially express Kv2.1 (but not Kv2.2), and that selective Kv2 blockade with guanxitoxin (GTx) drives these neurons to repetitively burst at theta frequency. We thus tested whether these features were also conserved in the non-human primate.
Methods:
To probe these cellular mechanisms, we utilized Kv2 immunohistochemistry from fixed macaque tissue and patch clamp recordings from live acute slices from mouse and macaque neocortex. We tested how PNs integrated complex network activity using two-photon glutamate uncaging to mimic naturalistic patterns of synaptic input onto the dendrites, and how GTx changed L5 PN input-output properties to probe the role of Kv2 channels.
Results:
The amplitude of the NMDA responses phase-locked to oscillations in the input rate were larger for slow (3 Hz) compared to fast (15 Hz) oscillations, in both rodent and primate neurons. Thus, the basal dendrites of L5 ET PNs preferentially amplify slow oscillations in neocortical network activity. We also found, consistent with rodents, Kv2.1 and Kv2.2 have a distinct laminar distribution across motor, prefrontal, temporal and visual macaque neocortex. Notably, larger layer 5 PNs in temporal and motor cortex were enriched in Kv2.1, but not Kv2.2. GTx induced repetitive burst firing in macaque L5 PNs with ET-like physiological properties, but this did not occur with non-ET L5 neurons.
Conclusions:
Combined, our work suggests that L5 ET neurons may have cell type specific properties that cause them to amplify slow oscillations and robustly propagate them in both mouse and primate neocortex.
Funding:
Supported by the U.S. National Institutes of Health (NIH) grants R01NS123959 to BK and ND and award number P51OD010425.