Jeehyun Kwag

Matching storage and recall: hippocampal spike timing-dependent plasticity and phase response curves

Hippocampal area CA3 is widely considered to function as an autoassociative memory. However, it is insufficiently understood how it does so. In particular, the extensive experimental evidence for the importance of carefully regulated spiking times poses the question as to how spike timing–based dynamics may support memory functions. Here, we develop a normative theory of autoassociative memory encompassing such network dynamics. Our theory specifies the way that the synaptic plasticity rule of a memory constrains the form of neuronal interactions that will retrieve memories optimally. If memories are stored by spike timing–dependent plasticity, neuronal interactions should be formalized in terms of a phase response curve, indicating the effect of presynaptic spikes on the timing of postsynaptic spikes. We show through simulation that such memories are competent analog autoassociators and demonstrate directly that the attributes of phase response curves of CA3 pyramidal cells recorded in vitro qualitatively conform with the theory.

The timing of external input controls the sign of plasticity at local synapses

The method by which local networks in the brain store information from extrinsic afferent inputs is not well understood. We found that the timing of afferent input can bidirectionally control the sign of spike timing–dependent plasticity at local synapses in rat hippocampus. This mechanism provides a means by which temporal information in external input can be encoded in the local matrix of synaptic weights.

Bidirectional control of spike timing by GABAA receptor-mediated inhibition during theta oscillation in CA1 pyramidal neurons

Precisely controlled spike times relative to &thetas;-frequency network oscillations play an important role in hippocampal memory processing. Here we study how inhibitory synaptic input during &thetas; oscillation contributes to the control of spike timing. Using whole-cell patch-clamp recordings from CA1 pyramidal cells in vitro with dynamic clamp to simulate &thetas;-frequency oscillation (5 Hz), we show that &ggr;-aminobutyric acid-A (GABAA) receptor-mediated inhibitory postsynaptic potentials (IPSPs) can not only delay but also advance the postsynaptic spike depending on the timing of the inhibition relative to the oscillation. Spike time advancement with IPSP was abolished by the h-channel blocker ZD7288 (10 μM), suggesting that IPSPs can interact with intrinsic membrane conductances to yield bidirectional control of spike timing.

Gating of NMDA receptor-mediated hippocampal spike timing-dependent potentiation by mGluR5

Hippocampal long-term potentiation (LTP) is believed to be important for learning and memory. Experimentally, the pairing of precisely timed pre- and postsynaptic spikes within a time window of ∼10 ms can induce timing-dependent LTP (tLTP), but the requirements for induction of tLTP change with development: in young rodents single postsynaptic spikes are sufficient to induce tLTP, whereas postsynaptic burst firing appears to be required in the adult. However, hippocampal neurons in vivo show theta-modulated single spike activities also in older hippocampus. Here we investigated the conditions for single spike pairing to induce tLTP at older CA3–CA1 synapses. We found that the pairing of single pre- and postsynaptic spikes could induce tLTP in older hippocampus when the postsynaptic neuronal membrane was depolarized and the pairing frequency exceeded ∼4 Hz. The spike frequency requirement is postsynaptic, as tLTP could still be induced with presynaptic stimulation at 1 Hz as long as the postsynaptic spike frequency exceeded ∼4 Hz, suggesting that postsynaptic theta-frequency activity is required for the successful induction of tLTP at older CA3–CA1 synapses. The induction of tLTP was blocked by an NMDA receptor antagonist and by the selective mGluR5 blockers, MPEP and MTEP, whereas activation of mGluR1 and mGluR5 by DHPG relieved the postsynaptic spike frequency requirement for tLTP induction. These results suggest that activation of mGluR5 during single-spike pairing at older CA3–CA1 synapses gates NMDA receptor-dependent tLTP.

Phase of firing as a local window for efficient neuronal computation: tonic and phasic mechanisms in the control of theta spike phase.

The nature of the neural code remains a central issue of contention in neuroscience. Firing rate based schemes have dominated thinking for most of the past century, but there is a growing acceptance that temporal patterns of neuronal activity have an important role to play, at least in some systems and circumstances. Neuronal oscillations provide a central pillar in the evidence supporting temporal coding, perhaps because temporal codes can ultimately be understood only in the context of population activity and oscillations are at once experimentally accessible and analytically tractable. In the many roles proposed for oscillatory activity, a uniting theme is the control of spike timing, which can broadly be considered on two timescales. On the one hand, fast oscillations may be important in promoting precise synchronization of activity across cells, by providing millisecond windows of enhanced spike probability. Slow oscillations, on the other hand, can provide a broader temporal scaffold, against which other inputs, both tonic and phasic, can determine spike timing on the order of milliseconds to tens of milliseconds. Again, this could be important for synchronization of activity, but equally, could be used to control spike order, for coding, or plasticity purposes, or could be used to desynchronize discrete assemblies, enabling parallel processing. Here, we describe the cellular mechanisms underlying this broader timescale process in the hippocampus, specifically focusing on the effect of tonic and phasic inputs on the control of spike timing in single hippocampal neurons during theta oscillations and the implications for information coding and storage.

Frequency dependence of CA3 spike phase response arising from h-current properties

The phase of firing of hippocampal neurons during theta oscillations encodes spatial information. Moreover, the spike phase response to synaptic inputs in individual cells depends on the expression of the hyperpolarization-activated mixed cation current (Ih), which differs between CA3 and CA1 pyramidal neurons. Here, we compared the phase response of these two cell types, as well as their intrinsic membrane properties. We found that both CA3 and CA1 pyramidal neurons show a voltage sag in response to negative current steps but that this voltage sag is significantly smaller in CA3 cells. Moreover, CA3 pyramidal neurons have less prominent resonance properties compared to CA1 pyramidal neurons. This is consistent with differential expression of Ih by the two cell types. Despite their distinct intrinsic membrane properties, both CA3 and CA1 pyramidal neurons displayed bidirectional spike phase control by excitatory conductance inputs during theta oscillations. In particular, excitatory inputs delivered at the descending phase of a dynamic clamp-induced membrane potential oscillation delayed the subsequent spike by nearly 50 mrad. The effect was shown to be mediated by Ih and was counteracted by increasing inhibitory conductance driving the membrane potential oscillation. Using our experimental data to feed a computational model, we showed that differences in Ih between CA3 and CA1 pyramidal neurons could predict frequency-dependent differences in phase response properties between these cell types. We confirmed experimentally such frequency-dependent spike phase control in CA3 neurons. Therefore, a decrease in theta frequency, which is observed in intact animals during novelty, might switch the CA3 spike phase response from unidirectional to bidirectional and thereby promote encoding of the new context.

M-channels modulate the intrinsic excitability and synaptic responses of layer 2/3 pyramidal neurons in auditory cortex.

Neurons in the auditory cortex are believed to utilize temporal patterns of neural activity to accurately process auditory information but the intrinsic neuronal mechanism underlying the control of auditory neural activity is not known. The slowly activating, persistent K(+) channel, also called M-channel that belongs to the Kv7 family, is already known to be important in regulating subthreshold neural excitability and synaptic summation in neocortical and hippocampal pyramidal neurons. However, its functional role in the primary auditory cortex (A1) has never been characterized. In this study, we investigated the roles of M-channels on neuronal excitability, short-term plasticity, and synaptic summation of A1 layer 2/3 regular spiking pyramidal neurons with whole-cell current-clamp recordings in vitro. We found that blocking M-channels with a selective M-channel blocker, XE991, significantly increased neural excitability of A1 layer 2/3 pyramidal neurons. Furthermore, M-channels controled synaptic responses of intralaminar-evoked excitatory postsynaptic potentials (EPSPs); XE991 significantly increased EPSP amplitude, decreased the rate of short-term depression, and increased the synaptic summation. These results suggest that M-channels are involved in controlling spike output patterns and synaptic responses of A1 layer 2/3 pyramidal neurons, which would have important implications in auditory information processing.

Dendritic-targeting interneuron controls spike timing of hippocampal CA1 pyramidal neuron via activation of Ih

Accurate spike timing of hippocampal CA1 pyramidal neurons relative to the on-going theta-frequency network oscillations is important in hippocampal spatial information and memory processing. Accumulating evidence suggests that inhibitory interneurons are important in regulating the activity of pyramidal neurons in the local hippocampal circuit. Interneurons synapse mostly onto the dendrites of CA1 pyramidal neurons where they are believed to take part in dendritic computation. However, it remains unclear how the diverse types of interneurons targeting different dendritic domains of pyramidal neurons differentially contribute to the precise control of spike timing during network oscillation. Here, using a full-morphology multi-compartment model of CA1 pyramidal neuron, we find that phasic inhibitory inputs during theta oscillation can precisely control spike timing of CA1 pyramidal neurons by not only delaying but also advancing the spike times. In addition, we report that the biophysical mechanism underlying the spike time advancement caused by inhibitory input is due to the hyperpolarization-activated mixed cation current (I(h)) in pyramidal neuron dendrites. Thus, a wide variety of interneuron types targeting different dendritic locations of pyramidal neuron activate dendritic I(h) to influence spike timing of pyramidal neuron during theta oscillation. This suggests an important functional role of dendritic-targeting interneurons in hippocampal spike timing-based information processing.

GABAA receptor-mediated feedforward and feedback inhibition differentially modulate hippocampal spike timing-dependent plasticity

Synaptic plasticity is believed to play an important role in hippocampal learning and memory. The precise and relative timing of pre- and postsynaptic activity has been shown to determine the sign and amplitude of hippocampal synaptic plasticity through spike timing-dependent plasticity (STDP). While most studies on STDP have mainly focused on excitatory synapses, neural networks are composed not only of excitatory synapses, but also of inhibitory synapses. Interneurons are known to make inhibitory synaptic connections with hippocampal CA1 pyramidal neurons through feedforward and feedback inhibitory networks. However, the roles of different inhibitory network structures on STDP remain unknown. Using a simplified hippocampal network model with a deterministic Ca(2+) dynamics-dependent STDP model, we show that feedforward and feedback inhibitory networks differentially modulate STDP. Moreover, inhibitory synaptic weight and synaptic location influenced the STDP profile. Taken together, our results provide a computational role of inhibitory network in STDP and in memory processing of hippocampal circuits.

M-type potassium conductance controls the emergence of neural phase codes: a combined experimental and neuron modelling study

Rate and phase codes are believed to be important in neural information processing. Hippocampal place cells provide a good example where both coding schemes coexist during spatial information processing. Spike rate increases in the place field, whereas spike phase precesses relative to the ongoing theta oscillation. However, what intrinsic mechanism allows for a single neuron to generate spike output patterns that contain both neural codes is unknown. Using dynamic clamp, we simulate an in vivo-like subthreshold dynamics of place cells to in vitro CA1 pyramidal neurons to establish an in vitro model of spike phase precession. Using this in vitro model, we show that membrane potential oscillation (MPO) dynamics is important in the emergence of spike phase codes: blocking the slowly activating, non-inactivating K+ current (IM), which is known to control subthreshold MPO, disrupts MPO and abolishes spike phase precession. We verify the importance of adaptive IM in the generation of phase codes using both an adaptive integrate-and-fire and a Hodgkin–Huxley (HH) neuron model. Especially, using the HH model, we further show that it is the perisomatically located IM with slow activation kinetics that is crucial for the generation of phase codes. These results suggest an important functional role of IM in single neuron computation, where IM serves as an intrinsic mechanism allowing for dual rate and phase coding in single neurons.