Construcción del Sistema Institucional de Evaluación (S.I.E) en la Institución Educativa

Two possible, nonexclusive sources of ripple-coherent EPSCs are conceivable.

CA3 coupling First, they could represent input from synaptically coupled CA3 pyra-

midal neurons. Indeed, phase-coupling of CA3 pyramidal cell spikes with CA1 field ripples has been demonstrated in vitro (Both et al., 2008), although in vivo locking is limited to slow ripples (<140 Hz; Csicsvari et al., 1999a Fig. 4; Sullivan et al., 2011, Fig. 8). We found ripple-modulated and locked EPSCs also in CA1 minislices, thus ruling out this possibility as theonlyorigin of ripple-locked EPSCs. Although observa- tion of SWR in minislices is not new (Maier et al., 2003; Nimmrich et al., 2005) our analysis shows that the timing and polarity of ripple-associated currents in minislices resemble those in full slices, thus supporting the idea that minislice SWRs display the full phenotypic range of the original phenomenon.

A fine-grained approach to test the influence of CA3 output on CA1 ripples was pioneered by Nakashiba et al. (2008). They reported a tetanus-toxin-based triple transgenic mouse that allows reversible inhibition of CA3 pyramidal cells by a two week withdrawal of doxycycline from the diet. Although comparably slow, this is more targeted than pharmacological inhibition or tissue lesions. Importantly, it affects the whole cell and not just one receptor subtype as was the case with deletion of the NMDAR gene in earlier work from the same lab (Tsien et al., 1996). Following up, Nakashiba et al. (2009) showed that CA1 ripples persisted after silencing CA3 input. These surviving “mutant” ripples displayed lower oscillation frequency on average (_∼120 Hzvs. 148 Hz), but during those of the mutant ripples that fell into the faster ripple frequency band, the experience-associated correlation of CA1 cell pair fir- ings was maintained (their Fig. 3F). It is not clear, though, which signal was the immediate trigger for the CA1 network to generate mutant ripples. Feasible inputs might arise from entorhinal cortex or thalamus (Nakashiba et al., 2009). Collectively, though Schaffer collateral input onto CA1 may be obligatory for the transfer of infor- mation involved in memory consolidation, transmission from CA3 to CA1 does not seem to be required for the occurrence of ripple oscillations in CA1 (see also Buzsáki et al., 1992).

Local CA1 origin A second framework to explain the origin of ripples posits their

purely local emergence, as a result of recurrent synaptic input alone. Through paired recordings, Deuchars and Thomson (1996) found that recurrent excitatory connec- tivity among CA1 pyramidal cells is mediated by synapses between the axon and the basal dendrite. Their measurements in rat slices point at a frequency of one in 100 random pairs, considerably lower than 1 in 16 for the CA3-CA1 pathway but within a factor two of the CA3 recurrence (1 in 50-100 after Miles and Wong, 1986; guinea pig slices). Complementary anatomy work on one pair showed that in spite of the cells being connected at only two sites, both on third-order basal dendrites (with all the implied synaptic filtering), the postsynaptic EPSP was large (1.5 mV amplitude). Of note, mouse tissue has a larger neuronal packing density, which is perhaps a reason why it seems more difficult to establish reliable models of SWR in vitro in the rat: Wu et al. (2005a) observe SWRs in only 40% of their thick CA3 slices and prop- agation towards CA1 is rarer (Liset Menéndez de la Prida, pers. comm.). The low firing rates of pyramidal cells result in insufficient statistics for correlational analysis with present tetrode technology, even in vivo (where rates are higher). This makes it difficult to test the functional utilization of the recurrent connections unveiled by ultrastructural anatomy combined with in vitro paired recordings. Our own results, especially our observation of ripple-coherent EPSCs in CA1 minislices are consis- tent with recurrent CA1 connectivity.

Lack of concomitant CA3 input could underlie the lower SWR occurrence in minislices. According to this idea the local CA1 network would be lifted less often to a transient self-sustaining oscillation (Stacey et al., 2011) from the synaptic noise due to CA1 alone. The reduction in amplitude could be connected with decreased CA3-induced inhibitory activity, but regrettably we lacked the experimental data (CA1 cells in the minislice held at the reversal potential of excitation) to test this hypoth- esis here.

Why are spikes so elusive? Perhaps it should not be surprising that there are so

few spikes during ripples. SWR are, after a fashion, the high-conductance states of the hippocampus (Destexhe et al., 2003), featuring 150% of the baseline conduc- tance (Bähner et al., 2011). The major effect of inhibitory inputs may be indeed of a shunting nature, making it difficult for excitation to elevate the membrane poten- tial closer to threshold.

Our cells held in voltage clamp reveal regular presynaptic spiking activity as PSCs. Yet the overall network activity is very sparse, both from excitation and inhibition. This is especially visible when in current clamp, where induced depolarization is needed to observe even a few spikes in a fraction of the cells during ripples. This is not exclusive of the mouse slice; for example Ellender et al. (2010) observe rates of 0.3 Hz across participating cells in rat slices (13% of all cells). We conceive two ways to account for this fact. One is that the code is very sparse and thus the prob- ability of choosing an assembly-participating cell is correspondingly small. This would also result in scarce postsynaptic currents. Proponents of the axonal coupling hypoth- esis (see below) would perhaps argue that spikes are generated in the axon, and do not necessarily propagate back to the soma, especially if the axon branches off a dendrite and not directly from the soma, or if the spike is generated in a thin axon collat- eral (Bähner et al., 2011).