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Key points: Stimulation of postsynaptic muscarinic receptors was shown to excite principal hippocampal neurons by modulating several membrane ion conductances.We show here that activation of postsynaptic muscarinic receptors also causes neuronal excitation by inhibiting Na+/K+‐ATPase activity.Muscarinic Na+/K+‐ATPase inhibition is mediated by two separate signalling pathways that lead downstream to enhanced Na+/K+‐ATPase phosphorylation by activating protein kinase C and protein kinase G.Muscarinic excitation through Na+/K+‐ATPase inhibition is probably involved in cholinergic modulation of hippocampal activity and may turn out to be a widespread mechanism of neuronal excitation in the brain. Stimulation of muscarinic cholinergic receptors on principal hippocampal neurons enhances intrinsic neuronal excitability by modulating several membrane ion conductances. The electrogenic Na+/K+‐ATPase (NKA; the 'Na+ pump') is a ubiquitous regulator of intrinsic neuronal excitability, generating a hyperpolarizing current to thwart excessive neuronal firing. Using electrophysiological and pharmacological methodologies in rat hippocampal slices, we show that neuronal NKA pumping activity is also subjected to cholinergic regulation. Stimulation of postsynaptic muscarinic, but not nicotinic, cholinergic receptors activates membrane‐bound phospholipase C and hydrolysis of membrane‐integral phosphatidylinositol 4,5‐bisphosphate into diacylglycerol (DAG) and inositol 1,4,5‐triphosphate (IP3). Along one signalling pathway, DAG activates protein kinase C (PKC). Along a second signalling pathway, IP3 causes Ca2+ release from the endoplasmic reticulum, facilitating nitric oxide (NO) production. The rise in NO levels stimulates cGMP synthesis by guanylate‐cyclase, activating protein kinase G (PKG). The two pathways converge to cause partial NKA inhibition through enzyme phosphorylation by PKC and PKG, leading to a marked increase in intrinsic neuronal excitability. This novel mechanism of neuronal NKA regulation probably contributes to the cholinergic modulation of hippocampal activity in spatial navigation, learning and memory. Key points: Stimulation of postsynaptic muscarinic receptors was shown to excite principal hippocampal neurons by modulating several membrane ion conductances.We show here that activation of postsynaptic muscarinic receptors also causes neuronal excitation by inhibiting Na+/K+‐ATPase activity.Muscarinic Na+/K+‐ATPase inhibition is mediated by two separate signalling pathways that lead downstream to enhanced Na+/K+‐ATPase phosphorylation by activating protein kinase C and protein kinase G.Muscarinic excitation through Na+/K+‐ATPase inhibition is probably involved in cholinergic modulation of hippocampal activity and may turn out to be a widespread mechanism of neuronal excitation in the brain. [ABSTRACT FROM AUTHOR]

• DGCs express sAHP-mediating currents associated with a burst-like phenotype. • The sAHP-mediating current is carried by at least Kv7 and Kir6 channels. • Perforant path-dentate gyrus LTP is amplified by blocking sAHP-mediating currents. The slow afterhyperpolarizing potential (sAHP) can silence a neuron for hundreds of milliseconds. Thereby, the sAHP determines the discharge behavior of many types of neurons. In dentate granule cells (DGCs), serving as a filter into the hippocampal network, mostly tonic or adapting discharge properties have been described. As under standard whole-cell recording conditions the sAHP is inhibited, we reevaluated the intrinsic functional phenotype of DGCs and the conductances underlying the sAHP, using gramicidine-perforated patch-clamp technique. We found that in 97/113 (86%) of the DGCs, a burst of action potentials (APs) to excitation ended by a large sAHP, despite continued depolarization. This result suggests that burst-like firing is the default functional phenotype of DGCs and that sAHPs are important for it. Indeed, burst-like firing DGCs showed a significantly higher sAHP-current (I sAHP) amplitude compared to spike-frequency adapting cells (16/113 = 14%). The I sAHP was mediated by K v 7 and K ir 6 channels by pharmacological inhibition using XE991 and tolbutamide, although heterogeneously among DGCs. The percent inhibition of I sAHP by these compounds also correlated with the AP number and AP burst length. Application of 100 µM nickel after XE991 and tolbutamide detected a third conductance contributing to burst-like firing and the sAHP, most likely mediated by T-type calcium channels. Lastly, medial perforant path-dentate gyrus long-term potentiation was amplified by XE991 and tolbutamide. In conclusion, the sAHP shapes intrinsic burst-like firing which, under physiological circumstances, could be controlled via cholinergic afferents and ATP metabolism. [ABSTRACT FROM AUTHOR]

Brain insults, such as trauma, stroke, anoxia, and status epilepticus (SE), cause multiple changes in synaptic function and intrinsic properties of surviving neurons that may lead to the development of epilepsy. Experimentally, a single SE episode, induced by the convulsant pilocarpine, initiates the development of an epileptic condition resembling human temporal lobe epilepsy (TLE). Principal hippocampal neurons from such epileptic animals display enhanced spike output in response to excitatory stimuli compared with neurons from nonepileptic animals. This enhanced firing is negatively related to the size of the slow afterhyperpolarization (sAHP), which is reduced in the epileptic neurons. The sAHP is an intrinsic neuronal negative feedback mechanism consisting normally of two partially overlapping components produced by disparate mechanisms. One component is generated by activation of Ca2+-gated K+ (KCa) channels, likely KCa3.1, consequent to spike Ca2+ influx (the KCa-sAHP component). The second component is generated by enhancement of the electrogenic Na +/K + ATPase (NKA) by spike Na + influx (NKA-sAHP component). Here we show that the KCa-sAHP component is markedly reduced in male rat epileptic neurons, whereas the NKA-sAHP component is not altered. The KCa-sAHP reduction is due to the downregulation of KCa3.1 channels, mediated by cAMP-dependent protein kinase A (PKA). This sustained effect can be acutely reversed by applying PKA inhibitors, leading also to normalization of the spike output of epileptic neurons. We propose that the novel acquired channelopathy" described here, namely, PKA-mediated downregulation of KCa3.1 activity, provides an innovative target for developing new treatments for TLE, hopefully overcoming the pharmacoresistance to traditional drugs. [ABSTRACT FROM AUTHOR]

The Na+/K+- ATPase (NKA) is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na+ and K+ electrochemical gradients across the plasmalemma of living cells. Numerous studies in non-neuronal tissues have shown that this transport mechanism is reversibly regulated by phosphorylation/dephosphorylation of the catalytic a subunit and/or associated proteins. In neurons, Na+/K+ transport by NKA is essential for almost all neuronal operations, consuming up to two-thirds of the neuron's energy expenditure. However, little is known about its cellular regulatory mechanisms. Here we have used an electrophysiological approach to monitor NKA transport activity in male rat hippocampal neurons in situ. We report that this activity is regulated by a balance between serine/threonine phosphorylation and dephosphorylation. Phosphorylation by the protein kinases PKG and PKC inhibits NKA activity, whereas dephosphorylation by the protein phosphatases PP-1 and PP-2B (calcineurin) reverses this effect. Given that these kinases and phosphatases serve as downstream effectors in key neuronal signaling pathways, they may mediate the coupling of primary messengers, such as neurotransmitters, hormones, and growth factors, to the NKAs, through which multiple brain functions can be regulated or dysregulated. [ABSTRACT FROM AUTHOR]

Abstract: In many types of CNS neurons, repetitive spiking produces a slow afterhyperpolarization (sAHP), providing sustained, intrinsically generated negative feedback to neuronal excitation. Changes in the sAHP have been implicated in learning behaviors, in cognitive decline in aging, and in epileptogenesis. Despite its importance in brain function, the mechanisms generating the sAHP are still controversial. Here we have addressed the roles of M‐type K+ current (IM), Ca2+‐gated K+ currents (ICa(K)'s) and Na+/K+‐ATPases (NKAs) current to sAHP generation in adult rat CA1 pyramidal cells maintained at near‐physiological temperature (35 °C). No evidence for IM contribution to the sAHP was found in these neurons. Both ICa(K)'s and NKA current contributed to sAHP generation, the latter being the predominant generator of the sAHP, particularly when evoked with short trains of spikes. Of the different NKA isoenzymes, α1‐NKA played the key role, endowing the sAHP a steep voltage‐dependence. Thus normal and pathological changes in α1‐NKA expression or function may affect cognitive processes by modulating the inhibitory efficacy of the sAHP. [ABSTRACT FROM AUTHOR]

During aging, the Ca 2+ -sensitive slow afterhyperpolarization (sAHP) of hippocampal neurons is known to increase in duration. This change has also been observed in the serotonergic cerebral giant cells (CGCs) of the pond snail Lymnaea stagnalis , but has yet to be characterized. In this article, we confirm that there is a reduction in firing rate, an increase in the duration of the sAHP, and an alteration in the strength and speed of spike frequency adaptation in the CGCs during aging, a finding that is compatible with an increase in the sAHP current. We go on to show that age-related changes in the kinetics of spike frequency adaptation are consistent with a reduction in Ca 2+ clearance from the cell, which we confirm with Ca 2+ imaging and pharmacological manipulation of the sodium calcium exchanger. These experiments suggest that the sodium calcium exchanger may be switching to a reverse-mode configuration in the CGCs during aging. [ABSTRACT FROM AUTHOR]

ABSTRACT Considerable advances have been made toward understanding the molecular signaling events that underlie memory acquisition and consolidation. In contrast, less is known about memory retrieval, despite its necessity for utilizing learned information. This review focuses on neuromodulatory and intracellular signaling events that underlie memory retrieval mediated by the hippocampus, for which the most information is currently available. Among neuromodulators, adrenergic signaling is required for the retrieval of various types of hippocampus-dependent memory. Although they contribute to acquisition and/or consolidation, cholinergic and dopaminergic signaling are generally not required for retrieval. Interestingly, while not required for retrieval, serotonergic and opioid signaling may actually constrain memory retrieval. Roles for histamine and non-opioid neuropeptides are currently unclear but possible. A critical effector of adrenergic signaling in retrieval is reduction of the slow afterhyperpolarization mediated by β1 receptors, cyclic AMP, protein kinase A, Epac, and possibly ERK. In contrast, stress and glucocorticoids impair retrieval by decreasing cyclic AMP, mediated in part by the activation of β2-adrenergic receptors. Clinically, alterations in neuromodulatory signaling and in memory retrieval occur in Alzheimer's disease, Down syndrome, depression, and post-traumatic stress disorder, and recent evidence has begun to link changes in neuromodulatory signaling with effects on memory retrieval. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT The slow afterhyperpolarizing current (sIAHP) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP, resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sIAHP, underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Understanding how epileptic seizures are initiated and propagated across large brain networks is difficult, but an even greater mystery is what makes them stop. Failure of spontaneous seizure termination leads to status epilepticus—a state of uninterrupted seizure activity that can cause death or permanent brain damage. Global factors, like changes in neuromodulators and ion concentrations, are likely to play major roles in spontaneous seizure cessation, but individual neurons also have intrinsic active ion currents that may contribute. The recently discovered gene Slack encodes a sodium-activated potassium channel that mediates a major proportion of the outward current in many neurons. Although given little attention, the current flowing through this channel may have properties consistent with a role in seizure termination. [ABSTRACT FROM PUBLISHER]

The effects of 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine (DA) and the muscarinic receptor agonist carbachol (CCh) on the voltage step-induced outward currents underlying afterhyperpolarization (AHP), consisting of a medium (ImAHP) and slow (IsAHP) component, were investigated in layer V pyramidal cells of the rat medial prefrontal cortex (mPFC). Whole-cell voltage clamp recordings were performed in vitro to quantitatively measure ImAHP and IsAHP and to examine their functional link to spike-frequency adaptation in the presence of agonists. CCh, 5-HT and NA all reduced the IsAHP and the spike adaptation, and, in some cells, replaced the IsAHP by the slow inward currents (IsADP) underlying the slow afterdepolarization (sADP). DA, however, failed to increase the frequency despite its comparable inhibition of the IsAHP over a range of concentrations. In order to test the neuromodulator agonists to see if they have additive actions on the IsAHP, the effects of co-application of two agonists that increased spike-frequency, 5-HT+NA, 5-HT+CCh and CCh+NA, all at the concentration 30 μM were examined. Specific combinations that included CCh showed additive effects on the slow afterpolarization currents, possibly via both inhibition of IsAHP and generation of IsADP. These findings suggest that neuromodulators have differential effects on the link between the IsAHP modulation and spike-frequency adaptation, and that they could exert additive effects on the slow aftercurrents following a strong excitation and, therefore, regulate the repetitive firing properties of the output cells of the rat mPFC. [Copyright &y& Elsevier]

Extra- and intracellular recordings from the CA1 region of rat hippocampal slices were employed to examine the role of the slow afterhyperpolarization (sAHP) in modulating the increases in neuronal excitability observed on increasing extracellular pH (pHo) from 7.4 to 7.7. In the majority of experiments, an antidromic conditioning stimulus applied in the presence ofd(–)-2-amino-5-phosphonopentanoic acid (d-APV), 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX) and bicuculline was employed to elicit a sAHP, and an antidromic test stimulus was applied during the sAHP. At pHo 7.4, a single conditioning stimulus elicited an action potential followed by a sAHP, which in turn inhibited the response to the test stimulus compared with the conditioning stimulus. Increasing the number of action potentials in the conditioning stimulus augmented the sAHP and further inhibited the test response, whereas isoproterenol inhibited the sAHP and prevented the relative inhibition of the test response. At pHo 7.7, a single conditioning stimulus elicited a burst of action potentials followed by a large sAHP, which in turn prevented the test stimulus from eliciting a burst of action potentials and, in extracellular recordings, further increased the inhibition of the test response. The latter effect did not solely reflect a high pHo-induced increase in the conditioning response (and, thus, the subsequent sAHP), but rather involved a more direct effect of high pHo to augment the sAHP. The results indicate that increasing pHo increases the excitability of CA1 neurons to an initial stimulus; however, a high pHo-dependent increase in the sAHP evoked by the initial stimulus limits the response to subsequent stimuli. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is associated with a dramatic decline in cognitive performance including hippocampal-dependent memory. We have investigated one feature of hippocampal activity related to memory, the γ (30–80 Hz)-frequency rhythm. Hippocampal slices from mice overexpressing the human amyloid precursor protein (APP)SWE mutation (TAS10) were compared at 8 and 16 months of age with wild-type littermates. In slices obtained from TAS10 mice aged 8 months the γ-frequency activity evoked with bath application of 200 nm kainate was significantly (P < 0.05; n = 8 slices, five animals) impaired (area power, 5956 ± 2487 µV2) compared to slices from wild-type animals (area power, 18 256 ± 7880 µV2). At 16 months of age there was no longer a significant difference (P > 0.05; n = 11 slices from five animals) between slices from TAS10 and wild-type control mice as the wild-type mice now exhibited a marked age-dependent reduction in γ-frequency activity (TAS10 area power, 5751 ± 1573 µV2; wild-type area power = 5379 ± 1454 µV2). Although no dense-core plaques were evident at 8 months there was detectable amyloid labelling in the TAS10 mice which might account for the deficits in γ activity observed at this age. Dense plaques were clearly evident in the TAS10, but not wild-type, mice at 16 months of age but no further reductions in γ-frequency activity were seen in the TAS10 mice. These data suggest that deficits in network function in Alzheimer's disease occur early and are not directly correlated to amyloid load. [ABSTRACT FROM AUTHOR]

A hippocampal stress response is mediated by the glucocorticoid and mineralocorticoid receptors and involves primarily delayed changes in hippocampal neuronal properties. In this study, we concentrate on stress-induced effects in CA1 neurons which include an enhancement of the slow afterhypolarization (sAHP), an increase in Ca2+ currents, specifically a presumed upregulation of the Cav1.2 subunit that mediates one type of the L-type Ca2+ currents (the Ls type), and a suppression of Ca2+ extrusion mechanism, manifested as a decrease in plasma membrane Ca2+-ATPase-1. The aim of our study lies in identifying a causal relationship between either or both of the changes in the Ca2+ dynamics system and the increase in the sAHP. We used a compartmental CA1 pyramidal neuron model that included detailed structural properties and biophysical mechanisms and was implemented in the NEURON simulation environment. The model incorporated equations for 16 types of ionic mechanisms, known to be present in CA1 pyramidal cells. Among these, both types of L-type Ca2+ current, one with normal activation kinetics (Ls) and one with additional prolonged openings (Lp), Ca2+-activated K+ conductances that underlie the AHP (I sAHP), and an integrated modeling equation for intracellular Ca2+ decay comprising all Ca2+ extrusion and buffering mechanisms were included. We found that the enhancement of sAHP could be explained partially not by an increase in Ls Ca2+ current, but rather by a decrease in the rate of intracellular Ca2+ decay. Furthermore, we suggest that an additional 50% increase in the I sAHP, along with the change in the Ca2+ extrusion mechanism, could fully explain the experimental findings. Previous modeling work from our lab suggested that there might be a causal effect between an increase in the Lp Ca2+ current and the aging-induced enhancement of the sAHP. However, a respective causal relationship between an increase in the Ls Ca2+ current and sAHP enhancement does not seem to exist, probably due to their differential contribution to intracellular Ca2+ levels. Experimental and computational evidence imply that aging and stress may induce different Ca2+-dependent cellular adaptations in CA1 neurons, which however, result in a similar phenotype of enhanced sAHP and subsequent decreased neuronal excitability. [Copyright &y& Elsevier]

Abstract: To test whether the slow afterhyperpolarization (sAHP) underlies the filter function of hippocampal granule cells (GCs), we compared the sAHP and spike frequency adaptation between granule cells and CA3 pyramidal cells (PCs) in hippocampal slices employing gramicidin perforated patch clamp recordings to best preserve the physiological cytoplasmic constitution. sAHPs were evoked in GCs and PCs with trains of action potentials in current clamp mode and showed comparable kinetics in both types of cells. The threshold frequency (500 ms firing) triggering a detectable sAHP was ∼10 Hz and ∼3 Hz in GCs and PCs, respectively. Half maximal sAHPs were reached at 30 Hz and 8 Hz in GCs and PCs, respectively. Maximal amplitude of sAHPs in GCs amounted to ∼3.5 mV, was ∼2-fold smaller than in PCs and could not be further increased with higher firing frequencies. The time course of sAHP activation was investigated with 50 Hz trains of action potentials applied for increasing durations. In both types of cells, the sAHP amplitude increased with a time constant of ∼400 ms. Nevertheless, sAHP never exceeded 4 mV in GCs but rose to ∼12 mV in PCs when cells fired for 3 s. The repetitive firing pattern of GCs and PCs was compared by injecting current amplitudes adjusted to provoke an initial firing frequency of 50 Hz. In GCs firing frequency declined slower (τ = 229 ms) and leveled off at a higher tonic firing frequency (28 Hz) when compared to PCs (τ = 126 ms, 18 Hz). We conclude that the intrinsic excitability of GCs cannot be primarily regulated by the sAHP. The sAHP in GCs is minimal most likely due to a small sAHP-channel density as well as to a more rigid control of intracellular Ca2+ levels. [Copyright &y& Elsevier]

The activation of the slow afterhyperpolarization (sAHP) in CA1 neurons was studied using whole-cell recordings in the presence of inhibitors of the fast and medium-duration AHPs. The amplitude of the slow afterhyperpolarization current (IsAHP) increased as a function of duration and magnitude of the depolarizing voltage pulse reflecting graded increases in Ca2+ influx through voltage-dependent Ca2+ channels. Therefore, the time constant for activation, τmax, determined from a family of IsAHPs as a function of pulse duration, was voltage dependent decreasing several-fold within the range of -20 to 20 mV and was dependent on extracellular [Ca2+]. The IsAHP displayed a pronounced rising phase that was well fit by a single exponential with a time constant, τrise, that was invariant of pulse duration, voltage, IsAHP amplitude, or external [Ca2+] and was significantly slower than the τmax. In current clamp, the magnitude of the sAHP increased with the number of evoked action potentials, yet τrise of the sAHP was invariant of action potential number and was similar to the τrise of the IsAHP recorded in voltage-clamp. The results suggest that there are two components to the development of the IsAHP, a rapid, voltage- and Ca2+-dependent step, the magnitude and rate of which reflects the voltage dependence of the Ca2+ channels, that triggers a second rate-limiting, voltage-independent process that dictates the slow IsAHP rise kinetics. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is associated with impairments of cognitive function both in humans and animal models. In diabetic rats cognitive deficits are related to alterations in activity-dependent synaptic plasticity in the hippocampus. Many similarities with the pathophysiology of normal brain aging have been noted, and the view emerges that the effects of diabetes on the brain are best described as “accelerated brain aging.”In the present study we examined whether CA1 pyramidal neurons from streptozotocin-induced diabetic rats display an increased slow afterhyperpolarization, often considered as a hallmark of neuronal aging. We found no differences in resting membrane potential, input resistance, membrane time-constant, and action potential amplitude and duration between CA1 pyramidal neurons from streptozotocin-induced diabetic and age-matched control rats. During a train of action potentials, however, there is an increased broadening of the action potentials in diabetic animals, so-called “spike broadening.” The amplitude of the slow afterhyperpolarization elicited by a train of action potentials is indeed increased in diabetic animals. Interestingly, when the slow afterhyperpolarization is elicited by a Ca2+ spike, there is no difference between control and diabetic rats. This indicates that the increased slow afterhyperpolarization in diabetes is likely to be due to an increased Ca2+ influx resulting from the increased spike broadening. These data underscore the notion that the diabetic brain at the neuronal level shares properties with brain aging. [Copyright &y& Elsevier]

Over the last two decades there has been significant progress towards understanding the neural substrates that underlie age-related cognitive decline. Although many of the exact molecular and cellular mechanisms have yet to be fully understood, there is consensus that alterations in neuronal calcium homeostasis contribute to age-related deficits in learning and memory. Furthermore, it is thought that the age-related changes in calcium homeostasis are driven, at least in part, by changes in calcium channel expression. In this review, we focus on the role of a specific class of calcium channels: L-type voltage-gated calcium channels (LVGCCs). We provide the reader with a general introduction to voltage-gated calcium channels, followed by a more detailed description of LVGCCs and how they serve to regulate neuronal excitability via the post burst afterhyperpolarization (AHP). We conclude by reviewing studies that link the slow component of the AHP to learning and memory, and discuss how age-related increases in LVGCC expression may underlie cognitive decline by mediating a decrease in neuronal excitability. [ABSTRACT FROM AUTHOR]

A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA , a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca2+-dependent translocation to the plasma membrane. This translocation suppresses neuronal activity via slow afterhyperpolarization (sAHP) and we found that the N75K mutant could not control sAHP during physiologically relevant neuronal activation. Simulations based on the obtained experimental results directly demonstrated an increased excitability in neurons expressing N75K mutant instead of wild type (WT) HPCA. In conclusion, our study identifies sAHP as a downstream cellular target perturbed by N75K mutation in DYT2 dystonia, demonstrates its impact on neuronal excitability, and suggests a potential therapeutic strategy to efficiently treat DYT2. • DYT2 dystonia-causing N75K mutant of hippocalcin has impaired Ca2+-sensitivity. • N75K mutation leads to a failure of hippocalcin signaling during neuronal activity. • N75K mutant is inefficient in gating of slow afterhyperpolarization in neurons. • N75K mutation increases neuronal excitability likely underlying DYT2 dystonia. [ABSTRACT FROM AUTHOR]