CA1 is the main source of afferents from the hippocampus, but the function of CA1 and its perforant path (PP) input remains unclear. In this thesis, Marr’s model of the hippocampus is used to investigate previously hypothesized functions, and also to investigate some of Marr’s unexplored theoretical ideas. The last part of the thesis explains the excitatory responses to PP activity in vivo, despite inhibitory responses in vitro. Quantitative support for the idea of CA1 as a relay of information from CA3 to the neocortex and subiculum is provided by constraining Marr’s model to experimental data. Using the same approach, the much smaller capacity of the PP input by comparison implies it is not a one-shot learning network. In turn, it is argued that the entorhinal-CA1 connections cannot operate as a short-term memory network through reverberating activity. The PP input to CA1 has been hypothesized to control the activity of CA1 pyramidal cells. Marr suggested an algorithm for self-organising the output activity during pattern storage. Analytic calculations show a greater capacity for self-organised patterns than random patterns for low connectivities and high loads, confirmed in simulations over a broader parameter range. This superior performance is maintained in the absence of complex thresholding mechanisms, normally required to maintain performance levels in the sparsely connected networks. These results provide computational motivation for CA3 to establish patterns of CA1 activity without involvement from the PP input. The recent report of CA1 place cell activity with CA3 lesioned (Brun et al., 2002. Science, 296(5576):2243-6) is investigated using an integrate-and-fire neuron model of the entorhinal-CA1 network. CA1 place field activity is learnt, despite a completely inhibitory response to the stimulation of entorhinal afferents. In the model, this is achieved using N-methyl-D-asparate receptors to mediate a significant proportion of the excitatory response. Place field learning occurs over a broad parameter space. It is proposed that differences between similar contexts are slowly learnt in the PP and as a result are amplified in CA1. This would provide improved spatial memory in similar but different contexts.

Sharp-wave ripples (SWR) generated in the CA3 subregion of the hippocampus (HC) during rest and sleep appear to coordinate memory consolidation to the neocortex (NC) by (1) reactivating small subsets of neurons (i.e. cell-assemblies) that encode recent waking experience and (2) propagating this information through the hippocampal formation. Although CA3 self-organizes SWRs in the absence of extrinsic inputs, cortical input to the HC conveyed by perforant path (PP) may influence SWR initiation nevertheless. Still, direct evidence that PP synaptic excitation can elicit SWRs is lacking, and it is unclear how this influence might compete or interact with self-organizing mechanisms. This dissertation tested the hypothesis that CA3's SWR pattern generator would self-organize its activity in the absence of PP input, but readily entrain to such input when present. Spontaneous SWRs (sSWR) occurred in slices prepared from the ventral portion of the mouse HC. Low-intensity electrical stimulation of PP afferents evoked short-latency field EPSPs in CA3 that were often followed by precisely timed evoked SWRs (eSWR). The network and single-cell characteristics of sSWRs and eSWRs were indistinguishable, indicative of a common patter generator. PP stimuli that followed sSWRs too closely usually failed to elicit eSWRs. Using a custom MATLAB/Simulink application to control PP stimulus timing during the ~250 ms sSWR refractory period revealed a statistically significant effect of stimulus delay (25, 50, 100, and 200 ms) on eSWR incidence, reaching a value of 0.72 (95% CI = [0.61, 0.81]) 200 ms after sSWR onset. In contrast, sSWR incidence at this time was much lower (95% CI = [0.015, 0.049]). Lesions targeting the direct PP input to CA3 substantially reduced eSWR incidence. In intact slices, eSWRs were readily evoked by stimulating the medial entorhinal cortex (MEC). In summary, PP input to CA3 from the MEC can initiate SWRs at times when self-organizing mechanisms generally cannot. Assuming sSWRs convey information to the NC, the ensuing refractory period might provide an opportunity for cortical feedback to reinforce the recently engaged cell-assembly. In the absence of such feedback, CA3 could revert to its default mode of self-organized replay.