A computational study on how theta modulated inhibition can account for the long temporal windows in the entorhinal–hippocampal loop
Introduction
The EC and hippocampus formation (HF) have been studied extensively yielding a wealth of data on cell types and their passive and active properties, network architecture and synaptic plasticity (Andersen et al., 2007, Cutsuridis et al., 2010b). HF contains principal excitatory neurons (GCs in DG and PCs in regions CA3 and CA1) and a large variety of excitatory and inhibitory interneurons (Freund and Buzsaki, 1996, Somogyi and Klausberger, 2005). The cells in different HF regions compute information differently. DG has been implicated in pattern separation (Marr, 1971, McNaughton and Morris, 1987, Wilson and McNaughton, 1993, Hasselmo and Wyble, 1997;), CA3 in pattern completion (Marr, 1971, McNaughton and Morris, 1987) and CA1 in novelty detection (Vinogradova, 2001) and mismatch of expectations (Hasselmo & Schnell, 1994). Local computation within each HF region takes time creating temporal windows of excitability, which are evident by local field potentials (LFPs) (Buzsaki, 2002).
Theta rhythm (4–10 Hz) is one such LFP (Alonso and Garcıa-Austt, 1987, Grastyan et al., 1959, Vanderwolf, 1969) and it has been shown to play an instrumental role in the coordination of neuronal firing in the entorhinal–hippocampal network (Buzsaki, 2002). Theta oscillations have also been implicated in the encoding and retrieval of episodic and spatial memories (Cutsuridis et al., 2008, Cutsuridis et al., 2010a, Cutsuridis and Hasselmo, 2012, Cutsuridis and Wenneckers, 2009, Hasselmo et al., 2002, Jensen and Lisman, 2005, Kunec et al., 2005) and disruption of them results in behavioral deficits (Winson, 1978). Theta rhythm in HF is paced by MS and diagonal band of Broca in the basal forebrain (Stewart and Fox, 1990, Winson, 1978), although several theta generators and theta dipoles seem to work independently in the hippocampus (Buzsaki, 2002, Montgomery et al., 2009). One such theta oscillator is recorded in the stratum lacunosum moleculare (SLM) in CA1, while two other are recorded in stratum moleculare (SM) in DG and stratum pyramidale (SP) in CA1 (Brankack, Stewart, & Fox, 1993). The SLM theta oscillator oscillates at opposite phase with the SM and SP oscillators, which oscillate in phase with each other (Brankack et al., 1993). Current source density studies (Brankack et al., 1993) have shown that theta in other layers in CA1 show intermediate to SLM and SM phase relations. Theta oscillations are also recorded in EC and show a phase inversion between layers I and II–V (Alonso and Garcıa-Austt, 1987, Mizuseki et al., 2009). EC layers II and III, which project to HF (DG, CA3 and CA1), oscillate in phase (Mizuseki et al., 2009), and this phase is similar to the one in CA1 SP (Mizuseki et al., 2009).
Excitation and inhibition in HF come in different flavors (Freund and Buzsaki, 1996, Klausberger and Somogyi, 2008). Inhibition in particular sculpts the activities of excitatory cells (GCs in DG and PCs in CA3 and CA1), thus allowing them to fire at particular temporal windows and phases with respect to external network oscillations (Klausberger and Somogyi, 2008, Mizuseki et al., 2009). At least 25 different types of inhibitory interneurons have been identified in regions DG, CA3 and CA1 of the hippocampus (Fuentealba et al., 2008a, Jinno et al., 2007, Klausberger et al., 2005, Somogyi and Klausberger, 2005, Somogyi et al., 2014, Vida, 2010). These include AACs, the perisomatic BCs and the dendritic BSCs, ivy (IVY), neurogliaform (NGL), OLMs and HC cells (Capogna, 2011, Freund and Buzsaki, 1996, Fuentealba et al., 2008a, Fuentealba et al., 2008b, Fuentealba et al., 2010). AACs innervate exclusively the initial axonal segment of the DG GCs and the CA3 and CA1 PCs, whereas BCs innervate their cell bodies and proximal dendrites (Somogyi and Klausberger, 2005, Vida, 2010). CA1’s BSCs and IVYs innervate the CA1 PC basal and oblique dendrites, whereas OLM and NGL cells target the apical dendritic tuft of CA3 and CA1 PCs aligned with the EC input (Capogna, 2011, Somogyi et al., 2014). The DG HC cells target the apical dendrites of the DG GCs (Vida, 2010).
DG, CA3 and CA1 cells discharge at different phases of theta oscillations (Capogna, 2011, Fuentealba et al., 2008a, Fuentealba et al., 2008b, Fuentealba et al., 2010, Klausberger and Somogyi, 2008, Mizuseki et al., 2009, Somogyi et al., 2014). CA1 OLMs, BSCs, IVYs and PCs fire at the trough of theta recorded in the CA1 SP, whereas CA1 AACs, BCs and NGLs fire at the peak of theta recorded in the CA1 SP (Fuentealba et al., 2008a, Fuentealba et al., 2008b, Fuentealba et al., 2010, Klausberger and Somogyi, 2008). CA3 AACs fire rhythmically around the peak of the theta oscillations recorded locally in CA3 (Viney et al., 2013), whereas CA3 BCs and PCs fire around the trough of the local CA3 theta with the PCs firing leading the BCs firing by few degrees (Tukker et al., 2013). CA3 OLMs, which are recurrently excited by the CA3 PCs should fire at the trough of CA3 theta right after the CA3 PCs. In addition to hippocampal cells, MS cell activities are theta modulated (Borhegyi et al., 2004, Dragoi et al., 1999, Stumpf et al., 1962). GABAergic MS neurons form two distinct populations exhibiting highly regular bursting activity that is coupled to either the trough or the peak of hippocampal theta waves (Borhegyi et al., 2004).
A recent seminal paper by Mizuseki et al. (2009) reported that the temporal delays between population activities in successive stages of the EC–hippocampal loop are considerably longer (about a half theta cycle) than previously reported during theta-associated behaviors and these delays could not be accounted for by axon conduction delays, synaptic delays and/or neuronal integration of feedforward excitatory inputs. They suggested that one of the potential physiological mechanisms for such long temporal delays is inhibition (see p. 277 in Mizuseki et al., 2009).
Building on their suggestion, we explored via computational modelling the role of theta modulated intra- and extra-hippocampal inhibition in the generation of longer than a theta half-cycle delays of neuronal excitability in successive hippocampal stages (DG, CA3 and CA1). We constructed a microcircuit model of the hippocampal formation (regions DG, CA3 and CA1) that used biophysical representations of the major cell types including GCs, CA3 and CA1 PCs and six types of interneurons: BCs, AACs, BSCs, OLMs, MCs and HC cells. Theta modulated inputs at alternate phases and strengths to the network came from the entorhinal cortex (layers 2 and 3) and the MS. The model simulated the timing of firing of different hippocampal cells with respect to the theta rhythm (Klausberger and Somogyi, 2008, Mizuseki et al., 2009, Somogyi et al., 2014, Tukker et al., 2013, Viney et al., 2013) and showed that the experimentally reported long temporal delays in the successive hippocampal regions (Mizuseki et al., 2009) are indeed due to theta modulated somatic and axonic inhibition. Our model also predicted that the phase at which the CA1 PCs fire with respect to the EC-L3 theta LFP (see Fig. 3) is determined by their increased dendritic excitability caused by the decrease of the axial resistance and the A-type K+ conductance along their dendritic trunk (Golding et al., 2005, Losonczy et al., 2008). The model proposed functional roles for the different inhibitory interneurons in the retrieval of the memory pattern by the DG, CA3 and CA1 network. Finally, the model led to a number of experimentally testable predictions that may provide a better understanding of the biophysical computations in the hippocampus.
Section snippets
Materials and methods
Fig. 1 in the main text illustrates the simulated microcircuit model of the DG-CA3-CA1 network. The model consists of 100 DG GCs, 2 DG MCs, 2 DG BCs, 1 HC, 100 CA3 PCs, 2 CA3 BCs, 1 CA3 AAC, 1 CA3 OLM cell, 100 CA1 PCs, 1 CA1 AAC, 2 CA1 BCs, and 1 CA1 BSC. All simulations were performed using NEURON (Hines & Carnevale, 1997) running on a PC under Linux.
Simplified morphologies including the soma, apical and basal dendrites and a portion of the axon, were used for each cell type. The biophysical
Results
Theta LFPs, as we mentioned before, have been shown to have an important role in the coordination of neuronal firing in the entorhinal–hippocampal network (Buzsaki, 2002). Theta LFPs, which are intracortical EEG population activities at the theta frequency (4–10 Hz) (Buzsaki, 2002), consist of rhythmic sources and sinks in regions CA3, and CA1 and DG (Brankack et al., 1993, Somogyi et al., 2014). Sinks are associated with great influx of cations from the extracellular into the intracellular
General issues
A detailed biophysical model of the hippocampal DG, CA3 and CA1 microcircuitries has been presented, which describes how the experimentally recorded theta phase separation of DG-GC, CA3-PC and CA1-PC and six different types of excitatory and inhibitory interneuronal activities recorded in DG, CA3 and CA1 at opposite half-cycles of theta (Klausberger and Somogyi, 2008, Mizuseki et al., 2009, Somogyi et al., 2014, Tukker et al., 2013, Viney et al., 2013) can explain the long temporal windows of
Acknowledgments
First author (Vassilis Cutsuridis) conceived, developed and implemented the model, designed experiments and model, designed experiments and model refinements, performed all data analysis and wrote the paper. Second author (Panayiota Poirazi) designed experiments and model refinements, supervised the work and revised the text of the paper. Authors would like to thank Guyri Buzsaki and Michael Hasselmo for their comments to an earlier version of this manuscript. Authors would also like to thank
Glossary
- DG
- dentate gyrus
- PC
- pyramidal cell
- BC
- basket cell
- AAC
- axo-axonic cell
- BSC
- bistratified cell
- OLM
- oriens lacunosum-moleculare cells
- MC
- mossy cell
- HC
- hilar perforant path associated cell
- EC
- entorhinal cortex
- MS
- medial septum
- HF
- hippocampal formation
- LFP
- local field potential
- SP
- stratum pyramidale
- NGL
- neurogliaform cell
- IVY
- ivy cell
- GCL
- granule cell layer
- ML
- molecular layer
- SL
- stratum lucidum
- SO
- stratum oriens
- LTP
- long term potentiation
- EC-L2
- entorhinal cortex, layer 2
- EC-L3
- entorhinal cortex, layer 3
- SLM
- stratum lacunosum moleculare
- SM
- stratum
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