Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus

Abstract

The behaviour-contingent rhythmic synchronization of neuronal activity is reported by local field potential oscillations in the theta, gamma and sharp wave-related ripple (SWR) frequency ranges. In the hippocampus, pyramidal cell assemblies representing temporal sequences are coordinated by GABAergic interneurons selectively innervating specific postsynaptic domains, and discharging phase locked to network oscillations. We compare the cellular network dynamics in the CA1 and CA3 areas recorded with or without anaesthesia. All parts of pyramidal cells, except the axon initial segment, receive GABA from multiple interneuron types, each with distinct firing dynamics. The axon initial segment is exclusively innervated by axo-axonic cells, preferentially firing after the peak of the pyramidal layer theta cycle, when pyramidal cells are least active. Axo-axonic cells are inhibited during SWRs, when many pyramidal cells fire synchronously. This dual inverse correlation demonstrates the key inhibitory role of axo-axonic cells. Parvalbumin-expressing basket cells fire phase locked to field gamma activity in both CA1 and CA3, and also strongly increase firing during SWRs, together with dendrite-innervating bistratified cells, phasing pyramidal cell discharge. Subcellular domain-specific GABAergic innervation probably developed for the coordination of multiple glutamatergic inputs on different parts of pyramidal cells through the temporally distinct activity of GABAergic interneurons, which differentially change their firing during different network states.

Keywords: GABA; inhibition; interneuron; oscillation; synapse.

Figure 1.

Schematic of the spatial and temporal relationships between pyramidal cells and eight types of GABAergic interneuron in the CA1 area. Top: the main synaptic connections of pyramidal cells (red, middle), three types of CCK-expressing cells (basket cell, perforant path-associated cell, Schaffer collateral-associated cell), ivy cells and PV-expressing basket, axo-axonic, bistratified and O-LM interneurons. The other 13 defined types of interneuron are not shown; ACh, acetycholine. The firing probability histograms are averages from several cells of the same type recorded in anaesthetized rats; note different scales for the y-axis and schematic LFP oscillations (black). During theta and ripple oscillations, interneurons innervating different domains of pyramidal cells fire with distinct patterns. Their firing is coupled to field gamma oscillations to varying degrees (averages of several cells of each type). The soma and dendrites are innervated in parallel by both CCK- or PV-expressing cells, which show different temporal dynamics. One key feature is that during theta, pyramidal cell firing probability is lowest at the peak of the pyramidal layer LFP, when axo-axonic cells innervating the axon initial segment fire maximally and the sum of CCK- and PV-expressing basket cell firing probability is also maximal. The cooperative action of these three GABAergic cell types suppresses pyramidal cell firing at the peak of theta. The dendrite-innervating cells show similar theta phase coupling, approximately counter-phased with the combined impact of perisomatic innervating cells. Bistratified and ivy cells innervating basal and small oblique pyramidal cell dendrites show the highest gamma coupling of their firing and most of their dendrites are in the input zone from CA3 pyramidal cells which fire strongly phase coupled to gamma oscillations in CA3. During ripple oscillations, GABA release to the axon initial segments from axo-axonic cells is withdrawn, allowing maximal pyramidal cell discharge synchronized by PV-expressing basket and bistratified cells. Connections among interneurons are not shown for clarity. (Data from [,–40].)

Figure 2.

Network activity-related firing patterns of the three major parvalbumin-expressing GABAergic neurons of stratum pyramidale in areas CA1 and CA3 of rats, with or without anaesthesia. (a) Theta was recorded in the pyramidal layer of CA1, except for the CA3 bistratified cell (TV32n, bottom). In CA1, PV-positive basket cells fire on the descending phase of CA1 pyramidal layer theta. Axo-axonic cells fire just after the theta peak, earlier than basket cells, and bistratified cells later, around the trough, at the highest firing probability of pyramidal cells. Note the increase in the frequency of theta oscillations without anaesthesia, but the nearly constant phase relationships in spite of increase in firing rates. (b) During SWRs, basket and bistratified cells strongly increase their firing rate, phase locked to the local oscillation, but axo-axonic cells reduce firing either with or without anaesthesia. Theta field potential, wide band; SWRs, LFP band-pass filtered (90–140; non-anaesthetised, 90–200 or 130–230 Hz) for ripple activity. Scale bars: 0.1 s; action potentials and field potential theta, 0.2 mV; ripples, 0.1 mV. (Data from [15,33,34,40], CA3 bistratified cell without anaesthesia (TJ Viney 2013, unpublished data).)

Figure 3.

Firing patterns related to network activity of CCK-expressing GABAergic neuronal types that collectively innervate the entire somato-dendritic domain of pyramidal cells and of dendrite-innervating O-LM and ivy cells in areas CA1 and CA3 of rat hippocampus. (a) Theta was recorded in the pyramidal layer of CA1. Ivy cells have been reported with and without anaesthesia; note the increase in theta frequency without anaesthesia, and the constant theta firing phase. All cell types, except basket cells in CA1 discharge with maximal probability near the trough of CA1 pyramidal layer theta, when pyramidal cells are most active in both areas under anaesthesia. (b) During SWR oscillations detected in CA1, on average, most cell types shown here in both areas do not change their firing rate; the exception is the perforant path-associated (pp-assoc.) cells in CA3, which increase their discharge. LFP, as for figure 2. Scale bars: 0.1 s; action potentials and field potential theta, 0.2 mV; ripples, 0.1 mV. (Data from [15,32,34,38,65].)