Presynaptic action potential modulation in a neurological channelopathy

Channelopathies are disorders caused by inherited mutations of specific ion channels. Neurological channelopathies in particular offer a window into fundamental physiological functions such as action potential modulation, synaptic function and neurotransmitter release. One such channelopathy Episodic Ataxia type 1 (EA1), is caused by a mutation to the gene that encodes for the potassium channel subunit Kv1.1. This channel is predominantly found in presynaptic terminals and EA1 mutations have previously been shown to result in increased neuronal excitability and neurotransmitter release. A possible reason is that presynaptic action potential waveforms are affected in EA1. Thus far, direct electrophysiological recording of presynaptic terminals has been limited to large specialised synapses e.g. mossy fibre boutons, or axonal blebs, unnatural endings of transected axons. This is not representative of the vast majority of small synapses found in the forebrain. Using a novel technique termed Hopping Probe Ion Conductance Microscopy (HPICM) I have been able to directly record action potentials from micrometer sized boutons in hippocampal neuronal culture. I have shown that in a knockout model of Kv1.1 and in a knockin model of the V408A EA1 mutation, presynaptic action potentials are broader than in wild type; however action potentials are unaffected in the cell body. Finally in some central synapses neurotransmitter release has been shown to depend on not only action potentials received in the presynaptic terminal, but also on slow subthreshold membrane potential fluctuations from the soma, termed analogue digital signalling. Kv1 channels have been implicated in partly mediating this form of signalling. I have shown via dual recordings from the soma and small presynaptic boutons, that analogue-digital signalling occurs in wild type and knockout of Kv1.1, but is abolished in the V408A EA1 mutation. This implies that analogue-digital signalling may not depend on Kv1.1 in particular, rather a change in the stoichiometry of the Kv1 channel

Anhedonia in epilepsy

BACKGROUND: Anhedonia, the impaired ability to experience pleasure, is a core feature of major depressive disorder, one of the most common comorbidities in epilepsy. It is also reported as a clinical feature independent of depression in a number of other neurological conditions. This study aimed to establish the prevalence of anhedonia in a sample of people with epilepsy, with and without a diagnosis of depression, and to examine the clinical and demographic characteristics of those who present with this symptom. METHODS: A consecutive sample of 211 people (118 female, 93 male, mean age 38.09 years) completed the Snaith-Hamilton Pleasure Scale (SHAPS) to determine the presence of anhedonia and the Hospital Anxiety and Depression Scale to determine levels of anxiety and depression. The majority of patients had focal epilepsy (n = 165), and the remaining patients had generalized epilepsy (n = 22), or unclassified epilepsy (n = 24). Sixteen percent of the sample had a clinical diagnosis of depression at the time of the study. RESULTS: Over one in three of the sample (35%) reported significant anhedonia on the SHAPS. While these patients were more likely to have a diagnosis of depression (p < 0.01), 30% of people without a diagnosis of depression also reported significant anhedonia. Difficulties gaining pleasure on 12 of the 14 items on the SHAPS were associated with cognitive difficulties, with those reporting an inability to feel pleasure on the item scoring significantly lower on tests of cognitive function than those who were able to gain pleasure. Of the three cognitive domains examined (overall intellectual ability, verbal memory, and processing speed), a poor memory had the strongest relationship; with lower memory function associated with an impaired ability to experience pleasure on 9 of the 14 items. CONCLUSION: While anhedonia is well recognized as a feature of depression, our data suggests that it can be present in up to a third of people with epilepsy who do not have a diagnosis of depression. Cognitive difficulties, particularly impaired memory function may mediate some features of anhedonia. The implications of these findings for the clinical management of anhedonia in people with epilepsy are discussed

Risk factors and outcome of hyperammonaemia in people with epilepsy

BACKGROUND: Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear. OBJECTIVE: To identify risk factors for hyperammonaemia and investigate the impact of its management on clinical outcomes. METHODS: We carried out a retrospective observational study of adults with epilepsy who had ammonia tested over a 3-year period. Hyperammonaemia was defined as ammonia level > 35 μmol/L. Patients were classified into two groups: hyperammonaemic and non-hyperammonaemic. Association analyses and linear regression analysis were used to identify risk factors for hyperammonaemia. RESULTS: We reviewed 1002 ammonia requests in total and identified 76 people with epilepsy who had ammonia concentration measured, including 26 with repeated measurements. 59/76 (78%) were found to have hyperammonaemia. There was borderline statistical significance of hyperammonaemia being less common in patients with an established monogenic/metabolic condition than in those with structural or cryptogenic epilepsy (P = 0.05). Drug resistance, exposure to stiripentol and oxcarbazepine were identified as risk factors for hyperammonaemia. We found a dose-dependent association between valproate and hyperammonaemia (P = 0.033). Clinical symptoms were reported in 22/59 (37%) of the hyperammonaemic group. Improved clinical outcomes with concurrent decrease in ammonia concentration were seen in 60% of patients following treatment adjustment. CONCLUSIONS: Drug resistance and exposure to stiripentol, oxcarbazepine or high-dose valproate are associated with an increased risk of hyperammonaemia. Clinicians should consider symptoms related to hyperammonaemia in patients on high-dose valproate or multiple antiseizure treatments. Prompt identification of hyperammonaemia and subsequent treatment adjustments can lead to improved clinical outcomes

Hippocampal theta activity during encoding promotes subsequent associative memory in humans

Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings

Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization

Although action potentials propagate along axons in an all-­or-­none manner, subthreshold membrane potential fluctuations at the soma affect neurotransmitter release from synaptic boutons. An important mechanism underlying analog-­digital modulation is depolarization-­mediated inactivation of presynaptic Kv1-­family potassium channels, leading to action potential broadening and increased calcium influx. Previous studies have relied heavily on recordings from blebs formed after axon transection, which may exaggerate the passive propagation of somatic depolarization. We recorded instead from small boutons supplied by intact axons identified with scanning ion conductance microscopy in primary hippocampal cultures, and asked how distinct potassium channels interact in determining the basal spike width and its modulation by subthreshold somatic depolarization. Pharmacological or genetic deletion of Kv1.1 broadened presynaptic spikes without preventing further prolongation by brief depolarizing somatic prepulses. A heterozygous mouse model of Episodic Ataxia type 1 harboring a dominant Kv1.1 mutation had a similar broadening effect on basal spike shape as deletion of Kv1.1;; however, spike modulation by somatic prepulses was abolished. These results argue that the Kv1.1 subunit is not necessary for subthreshold modulation of spike width. However, a disease-­associated mutant subunit prevents the interplay of analog and digital transmission, possibly by disrupting the normal stoichiometry of presynaptic potassium channels

Alternating hemiplegia of childhood: An electroclinical study of sleep and hemiplegia.

ObjectiveAlternating Hemiplegia of Childhood (AHC) is characterised by paroxysmal hemiplegic episodes and seizures. Remission of hemiplegia upon sleep is a clinical diagnostic feature of AHC. We investigated whether: 1) Hemiplegic events are associated with spectral EEG changes 2) Sleep in AHC is associated with clinical or EEG spectral features that may explain its restorative effect.MethodsWe retrospectively performed EEG spectral analysis in five adults with AHC and twelve age-/gender-matched epilepsy controls. Five-minute epochs of hemiplegic episodes and ten-minute epochs of four sleep stages were selected from video-EEGs. Arousals were counted per hour of sleep.ResultsWe found 1) hemispheric differences in pre-ictal and ictal spectral power (p = 0.034), during AHC hemiplegic episodes 2) 22% reduced beta power (p = 0.017) and 26% increased delta power (p = 0.025) during wakefulness in AHC versus controls. There were 98% more arousals in the AHC group versus controls (p = 0.0003).ConclusionsThere are hemispheric differences in spectral power preceding hemiplegic episodes in adults with AHC, and sleep is disrupted.SignificanceSpectral EEG changes may be a potential predictive tool for AHC hemiplegic episodes. Significantly disrupted sleep is a feature of AHC