Importantly, when the frequency was increased to 200 Hz, just 3 to 5 stimuli were sufficient to achieve

charge transfer comparable or even stronger PS-341 concentration than in the control (AAV-EGFP) neurons, although the onset of the response was delayed by several milliseconds. Thus, while the temporal precision of transmission suffered, downstream neurons still responded to high-frequency spikes. Even long-term potentiation was retained in Syt1-infected animals. When the mice were tested in a contextual fear conditioning paradigm, the results with TetTox injections largely confirmed previous investigations using more traditional methods. Recent memory was impaired in animals with the virus injected in the hippocampus and entorhinal cortex, whereas remote memory (tested ISRIB mouse several weeks after fear conditioning and the virus injection) was affected only in the prefrontal group. However, the results with Syt1-infected mice were surprising. While recent fear memory was seriously impaired after entorhinal

Syt1 knockdown, Syt1 hippocampal mice performed just like the controls. Animals with Syt1 infections in the prefrontal cortex were comparable to their TetTox peers. In summary, high-pass frequency filtering of spikes by Syt-1 did not matter much in the hippocampus but was devastating in both the entorhinal cortex and prefrontal cortex. On the basis of these spectacular findings, Xu and colleagues (2012) suggest that different spike coding mechanisms are at work in the three different brain Bumetanide regions. Hippocampal circuits can rely on bursts of spikes only, whereas the paleo- and neocortex networks need high temporal precision of single

spikes for coding, at least for the mediation of contextual fear memory. The authors’ account of their findings may indeed be right. Yet, one might also consider the possibility that it is not necessarily the precision of spikes that matters, but rather the extent to which each structure is able to communicate via high frequency bursts, and thus overcome the genetic manipulation. As the authors point out, cortical neurons can fire both single spikes and complex spike bursts and the bursts may be critical for spike transmission under certain conditions (Lisman, 1997). Unfortunately, there is no natural frequency border between single spikes and spike bursts and the interspike interval statistic reflects a renewal process where spiking history is critical (Harris et al., 2001). Traditionally, a spike burst is defined as three or more spikes with < 8 ms intervals (Ranck, 1973). In the hippocampus, spike doublets and triplets of pyramidal cells at such short intervals occur 14% and 3% of all spikes during exploration. A burst of 4 spikes is rare (0.4%) and 5 or more spikes is super rare (0.06%) although these fractions can increase several-fold during sleep.