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Key pointsr Activation of axonal dopamine D2 receptors (D2Rs) increases action potential (AP) threshold, and thus decreases neuronal excitability in layer II stellate cells of medial entorhinal cortex.r Endogenous dopamine release increases the AP threshold of stellate cells by activating D2Rs. r Activation of D2Rs shifts the activation curve of T-type Ca 2+ channels in a positive direction in a protein kinase A-dependent manner.r Immunofluorescence staining reveals the presence of T-type Ca 2+ channels and D2Rs in the axon initial segments (AISs).r This research makes the pioneering discovery of D2R-induced AP threshold plasticity in AISs of stellate cells. The findings are likely to have significant implications for understanding the cellular processes by which dopamine influences neuronal intrinsic excitability.Abstract Stellate cells in the medial entorhinal cortex (MEC) are considered to constitute the largest population of grid cells, which provide spatial representation to support animal estimation of location. Although dopaminergic fibres from the ventral tegmental area and substantia nigra pars compacta innervate the majority of the cortex, including the MEC, little is known about how dopamine modulates the function of MEC stellate cells. Because dopamine D2 receptors (D2Rs) are involved in spatial cognition and MEC contains high levels of D2Rs, we investigated how D2R activation modulates the neuronal intrinsic excitability of stellate cells. Electrophysiological Xueqin Jin received her bachelor's degree in Pharmaceutical Science in 2014 from Jilin University. Currently, she is a PhD student in the School of Pharmaceutical Sciences at Peking University under the supervision of Prof. Zhuo Huang. She is now focusing on how neurotransmitters modulate neuronal functional plasticity in spatial cognition and working memory.3364 X. Jin and others J Physiol 597.13recordings, optogenetics and molecular biology experiments were performed to investigate the mechanism in mice. Activation of axonal D2Rs, not dendritic or somatic D2Rs, elevated the action potential (AP) threshold and decreased the intrinsic excitability of stellate cells, which was caused by shifting rightward the activation properties of T-type Ca 2+ channels in a D2R-protein kinase A-dependent manner without affecting their steady-state inactivation curve. In support, immunofluorescence assays revealed colocalization of D2Rs and Ca v 3.2 calcium channels within the axon initial segment. These findings are likely to have significant implications for understanding the cellular processes by which dopamine influences neuronal excitability and they may also be applicable to other hippocampal and cortical regions as dopaminergic fibres innervate wide brain regions. Taken together, these findings provide a novel cellular mechanism by which D2Rs modulate AP threshold of stellate cells through T-type Ca 2+ channels in MEC, indicating that D2Rs of MEC play a vital role in modulating the information processing of stellate cells.

The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.

Behavioral timescale synaptic plasticity (BTSP) is a type of non-Hebbian synaptic plasticity reported to underlie place field formation in the hippocampal CA1 neurons. Despite this important function, the molecular mechanisms underlying BTSP are poorly understood. The αCalcium-calmodulin-dependent protein kinase II (αCaMKII) is activated by synaptic transmission-mediated calcium influx and its subsequent phosphorylation is central to synaptic plasticity. Because the activity of αCaMKII is known to outlast the event triggering phosphorylation, we hypothesized it could be involved in the extended timescale of the BTSP process. To examine the role of αCaMKII in BTSP, we performed whole-cell in-vivo and in-vitro recordings in CA1 pyramidal neurons from mice engineered to have a point mutation at the autophosphorylation site (T286A) causing accelerated signaling kinetics. Here we demonstrate a profound deficit in synaptic plasticity, strongly suggesting that αCaMKII signaling is required for BTSP. This study elucidates part of the molecular mechanism of BTSP and provides insight into the function of αCaMKII in place cell formation and ultimately learning and memory.

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