The hippocampal rate code: anatomy, physiology and theory

Abstract

Since the days of Cajal, the CA1 pyramidal cell has arguably received more attention than any other neuron in the mammalian brain. Hippocampal CA1 pyramidal cells fire spikes with remarkable spatial and temporal precision, giving rise to the hippocampal rate and temporal codes. However, little is known about how different inputs interact during spatial behavior to generate such robust firing patterns. Here, we review the properties of the rodent hippocampal rate code and synthesize work from several disciplines to understand the functional anatomy and excitation-inhibition balance that can produce the rate-coded outputs of the CA1 pyramidal cell. We argue that both CA3 and entorhinal inputs are crucial for the formation of sharp, sparse CA1 place fields and that precisely timed and dominant inhibition is an equally important factor.

Figure 1. Entorhinal projections to the hippocampus in the rat

The entorhinal cortex (EC) has traditionally been divided into 2 major subdivisions: the lateral entorhinal cortex (LEC) and the medial entorhinal cortex (MEC). However, there are also three bands that run perpendicular to the MEC/LEC divide: the dorsolateral, intermediate and ventromedial bands. The hippocampus has a septo-temporal axis (also called its long axis): it starts off at a septal, medial and dorsal location in each hemisphere and then arches backwards and outwards in a C-shape, ending up at a temporal, lateral and ventral location [18, 25]. The pathway projecting from the EC to the hippocampus is called the perforant path. This projection has a number of key organizing principles. There are topographic projections from the bands of the EC to the septo-temporal axis of the hippocampus. The dorsolateral band (encompassing parts of both the MEC and LEC) projects to the septal half of the hippocampus. The intermediate band projects to the third quarter of the hippocampus (projections not shown for sake of clarity). The ventromedial band goes to the most temporal quarter of the hippocampus [26]. A) Layer III pyramidal neurons in the LEC component of each band project to the distal portion of CA1 (cells distant from CA3) [25]. LEC layer III cells show poor spatial modulation [33]. B) Layer III pyramidal neurons in the MEC project to the proximal part of CA1 (cells closer to CA3) [25]. MEC layer III cells are spatially modulated: about half are head-direction cells, a quarter are grid cells and the rest are mixed [32]. C) In each of the three bands, layer II stellate cells of both the MEC and LEC project to the DG and CA3* [25]. This means that an individual DG or CA3 cell can be innervated by axons from both MEC and LEC. D) Granule cells in DG provide intra-hippocampal projections to CA3 [25, 80]. E) CA3 pyramidal cells provide input to CA1 via the Schaffer Collaterals. There is some topography in this projection: at each transverse level of the hippocampus, CA3 close to DG primarily project to distal CA1 cells, whereas CA3 cells closer to CA1 project to proximal CA1 cells [25]. * This figure shows projections from the EC to the hippocampus in the rat. In the mouse, however, CA3 does not receive its inputs from layer II of the EC. Instead, most projections to the mouse CA3 originate in layer III of both the MEC and LEC [73] (Table 2 and Box 2.4).

Figure 2. Synaptic organization of inputs to a single CA1 cell: source, number, strength and rate

A) Most inhibitory GABAergic inputs onto a single CA1 cell are from CA1 interneurons [48, 49]. B) Fast spiking putative interneurons corresponding to basket and axo-axonic cells project primarily to the proximal dendrites of the CA1 cell and to the cell body and axon. These cells fire at rates of at least 20 Hz in vivo during exploration [50-52]. However, few in vivo recordings have been made from interneurons with broad spikes such as O-LM neurons and other cells that project more heavily to the distal CA1 dendrites. Thus, the in vivo firing rate of these cells is unknown. C) Schematic showing representative spatial firing profiles of interneurons. Most of these cells fire at high rates and normally show little spatial modulation. However, recent studies have shown that some interneurons can also increase or decrease their firing rates in restricted regions of space [50-52]. D) The number of GABAergic synapses found across the CA1 cell body and dendrites [36]. E) The miniature inhibitory postsynaptic current (mIPSC) is relatively constant across the cell body and proximal dendrites of the CA1 cell [81]. The mIPSC magnitude at distal S-LM and basal S-O dendrites is unknown, as it is difficult to patch onto these very thin dendrites. F) The source of excitatory inputs to different dendritic regions of a CA1 cell [25]. G) The mean rate of excitatory inputs to a CA1 cell during exploration [32, 47]. H) Schematic showing representative spatial firing profiles of entorhinal and CA3 cell during exploration. Two-thirds of CA3 cells are silent, and the rest have sparse place fields. Entorhinal cells, on the other hand, encode space in a repeating grid pattern or encode head direction information [32]. I) The number of excitatory synaptic inputs onto dendritic spines at all locations along the dendritic tree of a CA1 cell. Note the larger number of putative CA3 inputs [36]. It should be pointed out that a small proportion of the excitatory synaptic inputs to a CA1 cell are from regions other than CA3 or EC [25]. J) The proportion of large, perforated synapses increases along the apical dendrite, peaking at the most distal synapses [39]. K) The number of AMPA receptors per perforated synapse peaks at the distal S-R dendrites, but then falls rapidly at the most distal dendrites in S-LM [38, 39]. L) As expected from the numbers in (I) and (J), the size of the miniature excitatory postsynaptic current (mEPSC) increases from proximal to distal S-R [42, 81]. However, no direct evidence exists for the value of this current in the most distal dendrites in S-LM as these dendrites are far too thin to patch on to. It is estimated that due to the decreased AMPA receptor count at these most distal synapses, the mEPSC would decrease in these distal dendrites [39]. M) The total number of inhibitory synapses on a CA1 neuron is far less than the number of excitatory synapses [36]. N) The mean firing rate of the inhibitory neurons is far greater than that of excitatory neurons [50-52]. Furthermore, entorhinal firing rates are much greater than CA3 rates [32, 47]. O) A product of the number of synapses times the firing rates yields an estimate of the net inhibitory and excitatory drive onto a CA1 cell. Conservative estimates suggest that the inhibitory drive may be at least twice as large as the excitatory drive. Note that this calculation does not factor in the efficacy, strength or short term dynamics of the synapses.

Figure 3. Excitation-inhibition balance onto a single CA1 pyramidal cell

Schematic representation of the relative influence of excitation and inhibition on the spatial selectivity of a place cell. The x-axis in all plots represents distance along a linear track. A) Perfectly balanced excitation and inhibition would lead to spikes at several points on the track due to random increases in excitation or decreases in inhibition. However, silent cells do not fire many spikes on the track [12]. B) Dominant inhibition would prevent random fluctuations in excitatory and inhibitory inputs from resulting in spikes. This could explain the observed, very rare firing of silent cells [12]. C) A synchronous increase in excitation at a particular point on the track can lead to excitation overcoming inhibition and the CA1 cell firing in a place-dependent manner [30]. D) A synchronous decrease in inhibition in a given region of space can also lead to the spatially modulated firing of a CA1 cell [50-52]. E) Experience-dependent changes in the excitatory inputs can lead to asymmetric place fields with higher firing rates [56-58].