Susana Ferrao Santos

Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation.

Intraneuronal accumulation of hyperphosphorylated protein tau in paired helical filaments together with amyloid-β peptide (Aβ) deposits confirm the clinical diagnosis of Alzheimer disease. A common cellular mechanism leading to the production of these potent toxins remains elusive. Here we show that, in cultured neurons, membrane depolarization induced a calcium-mediated transient phosphorylation of both microtubule-associated protein tau and amyloid precursor protein (APP), followed by a dephosphorylation of these proteins. Phosphorylation was mediated by glycogen synthase kinase 3 and cyclin-dependent kinase 5 protein kinases, while calcineurin was responsible for dephosphorylation. Following the transient phosphorylation of APP, intraneuronal Aβ accumulated and induced neurotoxicity. Phosphorylation of APP on Thr-668 was indispensable for intraneuronal accumulation of Aβ. Our data demonstrate that an increase in cytosolic calcium concentration induces modifications of neuronal metabolism of APP and tau, similar to those found in Alzheimer disease.

Expression of Human Amyloid Precursor Protein in Rat Cortical Neurons Inhibits Calcium Oscillations

Synchronous calcium oscillations are observed in primary cultures of rat cortical neurons when mature networks are formed. This spontaneous neuronal activity needs an accurate control of calcium homeostasis. Alteration of intraneuronal calcium concentration is described in many neurodegenerative disorders, including Alzheimer disease (AD). Although processing of amyloid precursor protein (APP) that generates Aβ peptide has critical implications for AD pathogenesis, the neuronal function of APP remains unclear. Here, we report that expression of human APP (hAPP) in rat cortical neurons increases L-type calcium currents, which stimulate SK channels, calcium-dependent K+ channels responsible for medium afterhyperpolarization (mAHP). In a neuronal network, increased mAHP in some neurons expressing hAPP leads to inhibition of calcium oscillations in all the cells of the network. This inhibition is independent of production and secretion of Aβ and other APP metabolites. In a neuronal network, reduction of endogenous APP expression using shRNA increases the frequency and reduces the amplitude of calcium oscillations. Altogether, these data support a key role for APP in the control of neuronal excitability.

Network excitability dysfunction in Alzheimer's disease: insights from in vitro and in vivo models.

UNLABELLED Recent reports have drawn attention to dysfunctions of intrinsic neuronal excitability and network activity in Alzheimer disease (AD). Here we review the possible causes of these basic dysfunctions and implications for AD, based on in vitro and in vivo findings. We then review the current therapeutic approaches particularly linked to the issue of neuronal excitability in AD. CONCLUSION AD is a complex, neurodegenerative disorder. Hippocampal synaptic dysfunction is an early feature of the degenerative process that is clearly linked to memory impairment, the first and major symptom of AD. A growing body of evidence points toward a dysfunction of neuronal networks. Intrinsic neuronal excitability, mainly through profound dysregulation of calcium homeostasis, appears to be largely affected. Consequently, neuronal communication is disturbed. Such cellular defects might underlie cognitive manifestations like fluctuations in cognitive impairment and might also explain several observations obtained with EEG, MEG, MRI, or PET studies, leading to the concept of a disconnection syndrome in AD.

Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception

The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation.

Inhibition of neuronal calcium oscillations by cell surface APP phosphorylated on T668

Adenoviral expression of human APP (hAPP), but not of hAPP deleted from its C-terminal intracellular domain, in rat cortical neurons abolishes spontaneous synchronous calcium oscillations. The intracellular domain of APP695 contains several residues that can be phosphorylated. Contrary to non-neuronal cells, a very high phosphorylation of APP on T668 is observed in neurons, which is mediated by JNK, GSK3 and Cdk5 protein kinases. JNK activity, modulated by GSK3, enhances the traffic of phosphorylated APP to nerve terminals, contrary to Cdk5. Here we show that inhibition of GSK3 and JNK restores calcium oscillations in an hAPP expressing neuronal network, whereas inhibition of Cdk5 does not. Expression of mutant hAPPT668A does not inhibit calcium oscillations, and the proportion of hAPPT668A at the plasma membrane is reduced by more than 50%. Altogether, these results indicate that the intracellular domain of APP is needed to inhibit neuronal calcium oscillations because GSK3/JNK phosphorylation of T668 controls APP trafficking at the plasma membrane.

Gamma-band oscillations preferential for nociception can be recorded in the human insula

Abstract Transient nociceptive stimuli elicit robust phase‐locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non‐nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma‐band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception‐evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non‐nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non‐nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150‐300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions.

Post-resection electrocorticography has no added value in epilepsy surgery.

Intra-operative electrocorticography (ECoG) has been traditionally used in the surgical management of medically refractory partial epilepsies to identify the limits of the epileptogenic zone. This retrospective study had as goal to evaluate whether tailored surgery based on the presurgical evaluation completed by intra-operative post-resection ECoG improves outcome. We reviewed 94 cases of epilepsy surgery with intra-operative ECoG and determined how many had an ECoG-guided surgical procedure in addition to the initial planned surgery. We also reviewed the presence of specific recurrent ECoG patterns of interictal epileptiform discharges (IED) in the exposed cortical surface, such as: electrographic seizures, bursts, intermittent spike waves, polyspikes or fast rhythms and continuous or quasi-continuous spiking. When performing a post-resection ECoG-tailored surgery, outcome did not improve in lesional or non-lesional epilepsy. Postoperative residual IED did not correlate with a poorer outcome. In our study, the persistence of post-resection IED on ECoG is not correlated with outcome in patients with lesional or non-lesional epilepsy.

Habituation of phase-locked local field potentials and gamma-band oscillations recorded from the human insula

Salient nociceptive and non-nociceptive stimuli elicit low-frequency local field potentials (LFPs) in the human insula. Nociceptive stimuli also elicit insular gamma-band oscillations (GBOs), possibly preferential for thermonociception, which have been suggested to reflect the intensity of perceived pain. To shed light on the functional significance of these two responses, we investigated whether they would be modulated by stimulation intensity and temporal expectation – two factors contributing to stimulus saliency. Insular activity was recorded from 8 depth electrodes (41 contacts) implanted in the left insula of 6 patients investigated for epilepsy. Thermonociceptive, vibrotactile, and auditory stimuli were delivered using two intensities. To investigate the effects of temporal expectation, the stimuli were delivered in trains of three identical stimuli (S1-S2-S3) separated by a constant 1-s interval. Stimulation intensity affected intensity of perception, the magnitude of low-frequency LFPs, and the magnitude of nociceptive GBOs. Stimulus repetition did not affect perception. In contrast, both low-frequency LFPs and nociceptive GBOs showed a marked habituation of the responses to S2 and S3 as compared to S1 and, hence, a dissociation with intensity of perception. Most importantly, although insular nociceptive GBOs appear to be preferential for thermonociception, they cannot be considered as a correlate of perceived pain.

Radiating Multiple Subpial Transection: Operative Techniques, Complications and Outcomes

Epilepsy is a neurologic disorder affecting nearly fifty million people worldwide [1]. In two thirds of the patients, seizures can be controlled with the right medication. Unfortunately, one third of the patients have drug-resistant epilepsy; for those patients, epilepsy surgery remains a possible life-transforming treatment option.

A case of anti-NMDA receptor encephalitis revealed by insular epilepsy

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system that typically manifests predominantly as a psychiatric disorder. However, other manifestations such as epileptic seizures, abnormal movements, and memory or language complications are not unusual. Here, we report the case of a young man who presented with a new-onset epilepsy, with ictal semiology suggestive of insular involvement; this hypothesis was supported by a PET-CT study. Anti-NMDAR antibodies were found in the CSF, confirming the diagnosis of anti-NMDAR encephalitis. A review of the literature reveals that epilepsy can be the first manifestation of NMDAR encephalitis, with a clear male predominance. Despite its rarity, neurologists should consider this diagnosis for any young patient developing a new-onset epilepsy with temporal or insular features, particularly if the patient is male. Other cognitive or behavioural signs, even very subtle, should also prompt diagnosis.