Fast activation of feedforward inhibitory neurons from thalamic input and its relevance to the regulation of spike sequences in the barrel cortex

Thalamocortical afferents innervate both excitatory and inhibitory cells, the latter in turn producing disynaptic feedforward inhibition, thus creating fast excitation–inhibition sequences in the cortical cells. Since this inhibition is disynaptic, the time lag of the excitation–inhibition sequence could be ∼2–3 ms, while it is often as short as only slightly above 1 ms; the mechanism and function of such fast IPSPs are not fully understood. Here we show that thalamic activation of inhibitory neurons precedes that of excitatory neurons, due to increased conduction velocity of thalamic axons innervating inhibitory cells. Developmentally, such latency differences were seen only after the end of the second postnatal week, prior to the completion of myelination of the thalamocortical afferent. Furthermore, destroying myelination failed to extinguish the latency difference. Instead, axons innervating inhibitory cells had consistently lower threshold, indicating they had larger diameter, which is likely to underlie the differential conduction velocity. Since faster activation of GABAergic neurons from the thalamus can not only curtail monosynaptic EPSPs but also make disynaptic ISPSs precede disynaptic EPSPs, such suppression theoretically enables a temporal separation of thalamically driven mono‐ and disynaptic EPSPs, resulting in spike sequences of ‘L4 leading L2/3’. By recording L4 and L2/3 cells simultaneously, we found that suppression of IPSPs could lead to deterioration of spike sequences. Thus, from the end of the second postnatal week, by activating GABAergic neurons prior to excitatory neurons from the thalamus, fast feedforward disynaptic suppression on postsynaptic cells may play a role in establishing the spike sequences of ‘L4 leading L2/3 cells’. Sensory information enters the cerebral cortex through the thalamus, first arriving at layer 4 (L4), where synapses are changed, and then reaching layer 2/3 (L2/3). Here we show that in mice thalamic inputs to L4 activate inhibitory neurons slightly earlier than excitatory neurons through axons with higher conduction velocity specifically targeting inhibitory neurons. Such preceding activation of inhibitory neurons, occurring only after the end of the second postnatal week, is likely to serve to establish sequenced activation of ‘L4 leading L2/3’ cells by generating precisely timed fast feedforward inhibition on both L4 and L2/3 neurons. Since the spiking order of L4 and L2/3 neurons determines the direct