Voltage dependence of subthreshold resonance frequency in layer II of medial entorhinal cortex

Center for Memory and Brain, Department of Psychology, Graduate Program for Neuroscience, Boston University, Boston, Massachusetts 02215, USA.
Hippocampus (Impact Factor: 4.16). 08/2012; 22(8):1733-49. DOI: 10.1002/hipo.22008
Source: PubMed


The resonance properties of individual neurons in entorhinal cortex (EC) may contribute to their functional properties in awake, behaving rats. Models propose that entorhinal grid cells could arise from shifts in the intrinsic frequency of neurons caused by changes in membrane potential owing to depolarizing input from neurons coding velocity. To test for potential changes in intrinsic frequency, we measured the resonance properties of neurons at different membrane potentials in neurons in medial and lateral EC. In medial entorhinal neurons, the resonant frequency of individual neurons decreased in a linear manner as the membrane potential was depolarized between -70 and -55 mV. At more hyperpolarized membrane potentials, cells asymptotically approached a maximum resonance frequency. Consistent with the previous studies, near resting potential, the cells of the medial EC possessed a decreasing gradient of resonance frequency along the dorsal to ventral axis, and cells of the lateral EC lacked resonant properties, regardless of membrane potential or position along the medial to lateral axis within lateral EC. Application of 10 μM ZD7288, the H-channel blocker, abolished all resonant properties in MEC cells, and resulted in physiological properties very similar to lateral EC cells. These results on resonant properties show a clear change in frequency response with depolarization that could contribute to the generation of grid cell firing properties in the medial EC.

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    • "By tuning the a parameter in Eq. 6, we were able to produce cells with differential resonance frequencies at both depolarized membrane potentials (a2,b2) and near a cell's resting membrane potential (a3, b3). Similar to previous data, (Shay et al., 2012; Erchova et al., 2004) model cells showed decreased resonance frequencies with depolarization. In addition, Izhikevich neurons responded to square wave hyperpolarizing currents with a prominent sag potential, and fired rebound spikes upon release from the step current (c). "
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    ABSTRACT: Rebound spiking properties of medial entorhinal cortex (mEC) stellate cells induced by inhibition may underlie their functional properties in awake behaving rats, including the temporal phase separation of distinct grid cells and differences in grid cell firing properties. We investigated rebound spiking properties using whole cell patch recording in entorhinal slices, holding cells near spiking threshold and delivering sinusoidal inputs, superimposed with realistic inhibitory synaptic inputs to test the capacity of cells to selectively respond to specific phases of inhibitory input. Stellate cells showed a specific phase range of hyperpolarizing inputs that elicited spiking, but non-stellate cells did not show phase specificity. In both cell types, the phase range of spiking output occurred between the peak and subsequent descending zero crossing of the sinusoid. The phases of inhibitory inputs that induced spikes shifted earlier as the baseline sinusoid frequency increased, while spiking output shifted to later phases. Increases in magnitude of the inhibitory inputs shifted the spiking output to earlier phases. Pharmacological blockade of h-current abolished the phase selectivity of hyperpolarizing inputs eliciting spikes. A network computational model using cells possessing similar rebound properties as found in vitro produces spatially periodic firing properties resembling grid cell firing when a simulated animal moves along a linear track. These results suggest that the ability of mEC stellate cells to fire rebound spikes in response to a specific range of phases of inhibition could support complex attractor dynamics that provide completion and separation to maintain spiking activity of specific grid cell populations.
    Neurobiology of Learning and Memory 09/2015; DOI:10.1016/j.nlm.2015.09.004 · 3.65 Impact Factor
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    • "The stellate cells in layer II of the medial entorhinal cortex have long been noted for their oscillatory character (Erchova et al., 2004) consisting of membrane potential oscillations (MPOs) and resonance properties (Engel et al., 2008; Giocomo and Hasselmo, 2008; Pastoll et al., 2012; Shay et al., 2012). More recently, it has been suggested that these cells participate in the grid-like firing fields with regard to an animals position in space. "
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    ABSTRACT: The neurons in layer II of the medial entorhinal cortex are part of the grid cell network involved in the representation of space. Many of these neurons are likely to be stellate cells with specific oscillatory and firing properties important for their function. A fundamental understanding of the nonlinear basis of these oscillatory properties is critical for the development of theories of grid cell firing. In order to evaluate the behavior of stellate neurons, measurements of their quadratic responses were used to estimate a second order Volterra kernel. This paper uses an operator theory, termed quadratic sinusoidal analysis (QSA), which quantitatively determines that the quadratic response accounts for a major part of the nonlinearity observed at membrane potential levels characteristic of normal synaptic events. Practically, neurons were probed with multi-sinusoidal stimulations to determine a Hermitian operator that captures the quadratic function in the frequency domain. We have shown that the frequency content of the stimulation plays an important role in the characteristics of the nonlinear response, which can distort the linear response as well. Stimulations with enhanced low frequency amplitudes evoked a different nonlinear response than broadband profiles. The nonlinear analysis was also applied to spike frequencies and it was shown that the nonlinear response of subthreshold membrane potential at resonance frequencies near the threshold is similar to the nonlinear response of spike trains.
    Frontiers in Cellular Neuroscience 08/2014; 8:239. DOI:10.3389/fncel.2014.00239 · 4.29 Impact Factor
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    • "Grid cell firing has been proposed to be generated within the MEC local circuit [2]–[5]. Cellular properties of MEC neurons such as subthreshold membrane potential oscillations (SMPOs) [2], [3], [6], resonance [6]–[8], input resistance [9], firing frequency adaptation [10] and persistent firing [11] may play an important role in grid cell firing. The SMPO frequency, the resonance frequency and the input resistance have been reported to vary systematically along the dorso-ventral (DV) axis and are suggested to underlie the gradient of spacing of grid cell firing fields at different positions along the DV axis [6], [9], [12], [13]. "
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    ABSTRACT: Mechanisms underlying grid cell firing in the medial entorhinal cortex (MEC) still remain unknown. Computational modeling studies have suggested that cellular properties such as spike frequency adaptation and persistent firing might underlie the grid cell firing. Recent in vivo studies also suggest that cholinergic activation influences grid cell firing. Here we investigated the anatomical distribution of firing frequency adaptation, the medium spike after hyperpolarization potential (mAHP), subthreshold membrane potential oscillations, sag potential, input resistance and persistent firing, in MEC layer II principal cells using in vitro whole-cell patch clamp recordings in rats. Anatomical distributions of these properties were compared along both the dorso-ventral and medio-lateral axes, both with and without the cholinergic receptor agonist carbachol. We found that spike frequency adaptation is significantly stronger in ventral than in dorsal neurons both with and without carbachol. Spike frequency adaptation was significantly correlated with the duration of the mAHP, which also showed a gradient along the dorso-ventral axis. In carbachol, we found that about 50% of MEC layer II neurons show persistent firing which lasted more than 30 seconds. Persistent firing of MEC layer II neurons might contribute to grid cell firing by providing the excitatory drive. Dorso-ventral differences in spike frequency adaptation we report here are opposite from previous predictions by a computational model. We discuss an alternative mechanism as to how dorso-ventral differences in spike frequency adaptation could contribute to different scales of grid spacing.
    PLoS ONE 09/2013; 8(9):e73904. DOI:10.1371/journal.pone.0073904 · 3.23 Impact Factor
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