Research Topics


Synaptic and Network Dynamics in the Prefrontal Cortex

Persistent activity in the prefrontal cortex (PFC) is recognized as a neural basis for working memory. The PFC consists of diverse populations of neurons with distinct physiology: e.g., intratelencephalic (IT) and subcortically-projecting (SC) pyramidal cells, fast-spiking, parvalbumin-expressing interneurons (FS-IN or PV-IN), regular-spiking, somatostatin-expressing interneurons (RS-IN or Sst-IN), and vasoactive intestinal peptide-expressing interneurons (VIP-IN). While persistent activity is a combined outcome of the complex organization of these populations as well as the synaptic dynamics within their connections, computational models developed to date have not adequately addressed short-term synaptic plasticity (STP) concurrent with persistent activity, despite its crucial and obvious importance in neuronal communication. We have hence investigated the synaptic dynamics of major excitatory and inhibitory connections constituting the PFC network, during a prolonged time period that covers the duration of working memory tasks and persistent activity in vivo. From this standpoint, we consider the contribution of empirically measured STP at PFC synapses to persistent activity, in the context of a balanced network model.

- Yoon JY et al. (2020) Disparities in short-term depression among prefrontal cortex synapses sustain persistent activity in a balanced network. Cerebral Cortex 30(1): 113-134


Presynaptic Mechanisms of Short-Term Plasticity

Short-term plasticity (STP) is essential for understanding information processing in a well-defined neuronal network. Without the knowledge of STP at individual synapses, brilliant achievements from connectomics studies would still be but a house of cards. As presynaptic terminals are the center of action for a variety of STP phenomena, we have studied presynaptic calcium and synaptic vesicle dynamics by exploiting the unique opportunities for quantitative analysis offered by the calyx of Held synapse, and elucidated the calcium clearance mechanisms at the late stages that render vesicles release-ready. We found Na+/Ca2+ exchangers (NC[K]X) and mitochondria to be major calcium clearance machineries that play essential roles in post-tetanic potentiation (PTP). Furthermore, we dissected two sequential steps of release with distinct pharmacology and kinetics, the characterization of which is essential for an understanding of the molecular mechanisms of neurotransmitter release and short-term plasticity. We are now studying calcium regulation in the late stages during synaptic vesicle maturation, and STP mechanisms, in more conventional, small synapses.

- Lee BJ et al. (2022) Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin Prog. Neurobiol. 208: 102182.
- Yang CH et al. (2021) Inter-spike mitochondrial Ca2+ release enhances high frequency synaptic transmission. J. Physiol. 599(5): 1567-1594.
- Lee JS et al. (2013) Superpriming of synaptic vesicles after their recruitment to the readily releasable pool. PNAS, 110(37): 15079-15084.
- Lee JS et al. (2012) Actin-dependent rapid recruitment of reluctant synaptic vesicles into a fast-releasing vesicle pool. PNAS, 109(13): E765-E774.


Synaptic Modulation of Neuronal Excitability in CA3

Recognition involves not only the simple retrieval of stored memory that is similar to what we perceive, but also the completion of the whole picture through recall of memories pertaining to partial or degraded sensory cues (pattern completion). On the other hand, we also need to catch small differences between similar contexts (pattern separation). It has been demonstrated that regional deletion of NMDA receptor gene, which is essential to memory formation, in the hippocampal dentate gyrus (DG) and CA3 regions respectively impairs pattern separation and pattern completion. The sole output of the DG is fed into the CA3 via mossy fibers (MFs); this implies that the two complementary cognitive functions are integrated in the CA3 region, but the cellular mechanism of such function remains elusive. The distal dendrites of CA3 pyramidal cells (CA3-PCs) receive inputs of sensory cues directly from the neighboring neocortical region via perforant pathway (PP), whereas proximal dendrites are innervated by MFs from DG that generate information relevant to pattern separation. Therefore, heterosynaptic interaction between MF and PP synaptic inputs in CA3-PCs is of crucial importance for understanding how CA3-PCs bind MF inputs with direct cortical inputs to resolve two complementary cognitive tasks. Investigating DG input-induced heterosynaptic modulation of direct cortical inputs, we found that MF input-induced repetitive somatic firings downregulate D-type K+ channels, Kv1.2, at distal dendrites, thereby enhancing the coupling between PP synaptic inputs to spike generation, which in turn facilitates memory formation triggered by direct cortical inputs. Because of the sparsity in DG-CA3 synapses, DG input-induced gating may help the CA3 region for sparse representation of direct cortical inputs and, subsequently, pattern separation. Now we investigate further the cognitive consequences of impairments in such heterosynaptic interactions.

- Eom K et al. (2021) Gradual decorrelation of CA3 ensembles associated with contextual discrimination learning is impaired by Kv1.2 insufficiency. Hippocampus(epub), https://doi.org/10.1002/hipo.23400
- Eom K et al. (2019) Intracellular Zn2+ signaling facilitates mossy fiber input-induced heterosynaptic potentiation of direct cortical inputs in hippocampal CA3 pyramidal cells. J. Neurosci. 39(20): 3812
- Yu W et al. (2018) mGluR5-dependent modulation of dendritic excitability in CA1 pyramidal neurons mediated by enhancement of persistent Na+ currents. 596(17): 4141-4156.
- Hyun JH et al. (2015) Kv1.2 mediates heterosynaptic modulation of direct cortical synaptic inputs in CA3 pyramidal cells. J Physiol. 593(16): 3617