Altered Neuronal Activity Research Articles

Modulation of Neocortical Development by Early Neuronal Activity: Physiology and Pathophysiology.

Animal and human studies revealed that patterned neuronal activity is an inherent feature of developing nervous systems. This review summarizes our current knowledge about the mechanisms generating early electrical activity patterns and their impact on structural and functional development of the cerebral cortex. All neocortical areas display distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, intermittent spontaneous activity is synchronized within small neuronal networks, becoming more complex with further development. This transition is accompanied by a gradual shift from electrical to chemical synaptic transmission, with a particular role of non-synaptic tonic currents before the onset of phasic synaptic activity. In this review article we first describe functional impacts of classical neurotransmitters (GABA, glutamate) and modulatory systems (e.g., acetylcholine, ACh) on early neuronal activities in the neocortex with special emphasis on electrical synapses, nonsynaptic and synaptic currents. Early neuronal activity influences probably all developmental processes and is crucial for the proper formation of neuronal circuits. In the second part of our review, we illustrate how specific activity patterns might interfere with distinct neurodevelopmental processes like proliferation, migration, axonal and dendritic sprouting, synapse formation and neurotransmitter specification. Finally, we present evidence that transient alterations in neuronal activity during restricted perinatal periods can lead to persistent changes in functional connectivity and therefore might underlie the manifestation of neurological and neuropsychiatric diseases.

The Role of Innate Immune System Receptors in Epilepsy Research.

Epilepsy is one of the most complex neurological disorders and its study requires a broad knowledge of neurology and neuroscience. It comprises a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures, and are often accompanied by cognitive deficits and mood disorder. This condition is one of the most common neurological disorders. Until recently, alterations of neuronal activities had been the focus of epilepsy research. This neurocentric emphasis did not address issues that arise in more complex models of epileptogenesis. An important factor in epilepsy that is not regulated directly by neurons is inflammation and the immune response of the brain. Recent evidence obtained in rodent epilepsy models supports the role of immune responses in the initiation and maintenance of epilepsy. Recognition of exogenous pathogens by the innate immune system is mediated by some pattern recognition receptors such as Toll-like receptors leading to cell activation and cytokine production. Currently, these receptors have been the focus of epilepsy studies looking to determine whether the innate immune activation is neuroprotective or neurotoxic for the brain. Here, we present the evidence in the literature of the involvement of key innate immune receptors in the development of epilepsy. We address some of the contradictory findings in these studies and also mention possible avenues for research into epilepsy treatments that target these receptors.

Enhanced fear and altered neuronal activation in forebrain limbic regions of CX3CR1-deficient mice

Mounting evidence supports immune dysfunction in psychiatric conditions such as post-traumatic stress disorder (PTSD). The association of immunomodulatory mechanisms with PTSD-relevant behavior and physiology is not well understood. Communication between neurons and microglia, resident immune cells of the central nervous system, is crucial for optimal regulation of behavior and physiology. In this regard, the fractalkine CX3CL1, secreted from neurons and its target, the microglial CX3CR1 receptor represent a primary neuron-microglia inter-regulatory system important for synaptic plasticity and function. The current study investigated the impact of CX3CR1 deficiency on behaviors relevant to PTSD, such as fear acquisition and memory, acoustic startle response and anxiety-like behavior. Morphological analysis of microglia and neuronal activation within PTSD-relevant forebrain nuclei regulating stress and fear behaviors was also conducted. CX3CR1-deficient (CX3CR1−/−) mice elicited increased fear acquisition as well as reinstatement of fear as compared to wild type (CX3CR1+/+) mice. Conditioned fear and extinction were not significantly different between genotypes. No significant differences were observed in unconditioned acoustic startle response between genotypes. CX3CR1−/− mice showed reduced anxiety-like behaviors as compared with CX3CR1+/+ mice. Morphological assessment of microglia showed region-selective effects of CX3CR1 deficiency, primarily within hypothalamic and cortical areas. Lastly, CX3CR1−/− mice elicited elevated neuronal activity in the PVN and the ventral tegmental-interpeduncular area following reinstatement of fear. Collectively, our data suggest that impaired CX3CR1 function may evoke region-selective alterations in forebrain circuits regulating stress, anxiety and fear, impacting behaviors relevant to disorders such as PTSD.

Attentional deficits and altered neuronal activation in medial prefrontal and posterior parietal cortices in mice with reduced dopamine transporter levels.

The executive control function of attention is regulated by the dopaminergic (DA) system. Dopamine transporter (DAT) likely plays a role in controlling the influence of DA on cognitive processes. We examined the effects of DAT depletion on cognitive processes related to attention. Mice with the DAT gene genetically deleted (DAT+/- heterozygotes) were compared to wild type (WT) mice on the Attentional Set-Shifting Task (ASST). Changes in neuronal activity during the ASST were shown with early growth response genes 1 and 2 (egr-1 and egr-2) immunohistochemistry in the medial prefrontal cortex (mPFC) and in the posterior parietal cortex (PPC). Heterozygotes were impaired in tasks that tax reversal learning, attentional-set formation and set-shifting. Densities of egr-2 labeled cells in the mPFC were lower in mutant mice when compared with wild-types in intradimensional shift of attention (IDS), extradimensional shift of attention and extradimensional shift of attention-reversal phases of the ASST task, and in PPC in the IDS phase of the task. The results demonstrate impairments of the areas associated with attentional functions in DAT+/- mice and show that an imbalance of the dopaminergic system has an impact on the complex attention-related executive functions.

Neuronal firing activity in the basal ganglia after striatal transplantation of dopamine neurons in hemiparkinsonian rats

The loss of nigral dopaminergic neurons and the resulting dopamine (DA) depletion in the striatum (STR) lead to altered neuronal activity and enhanced beta activity in various regions of the basal ganglia (BG) motor loop in patients with Parkinson’s disease and in rodents in the 6-hydroxydopamine (6-OHDA)-lesioned rat model. Intrastriatal DA graft implantation has been shown to re-innervate the host brain and restore DA input.Here, DA cell grafts were implanted into the STR of 6-OHDA-lesioned rats and the effect on neuronal activity under urethane anesthesia (1.4g/kg, injected intraperitoneally) was tested in the entopeduncular nucleus (EPN, the equivalent to the human globus pallidus internus), the output nucleus of the BG, and the globus pallidus (GP, the equivalent to the human globus pallidus externus), a key region in the indirect pathway.In animals, which were transplanted with cells derived from the ventral mesencephalon of embryonic day 12 rat embryos into the STR, the rotational behavior induced by DA agonists in 6-OHDA-lesioned rats was significantly improved. This was accompanied by alleviated EPN firing rate and reinstated patterns of neuronal activity in the GP and EPN. Analysis of oscillatory activity revealed enhanced beta activity in both regions, which was reduced after grafting.In summary these data indicate restoration of BG motor loop toward normal activity by DA graft integration.

PTEN Loss Increases the Connectivity of Fast Synaptic Motifs and Functional Connectivity in a Developing Hippocampal Network.

Changes in synaptic strength and connectivity are thought to be a major mechanism through which many gene variants cause neurological disease. Hyperactivation of the PI3K-mTOR signaling network, via loss of function of repressors such as PTEN, causes epilepsy in humans and animal models, and altered mTOR signaling may contribute to a broad range of neurological diseases. Changes in synaptic transmission have been reported in animal models of PTEN loss; however, the full extent of these changes, and their effect on network function, is still unknown. To better understand the scope of these changes, we recorded from pairs of mouse hippocampal neurons cultured in a two-neuron microcircuit configuration that allowed us to characterize all four major connection types within the hippocampus. Loss of PTEN caused changes in excitatory and inhibitory connectivity, and these changes were postsynaptic, presynaptic, and transynaptic, suggesting that disruption of PTEN has the potential to affect most connection types in the hippocampal circuit. Given the complexity of the changes at the synaptic level, we measured changes in network behavior after deleting Pten from neurons in an organotypic hippocampal slice network. Slices containing Pten-deleted neurons showed increased recruitment of neurons into network bursts. Importantly, these changes were not confined to Pten-deleted neurons, but involved the entire network, suggesting that the extensive changes in synaptic connectivity rewire the entire network in such a way that promotes a widespread increase in functional connectivity.SIGNIFICANCE STATEMENT Homozygous deletion of the Pten gene in neuronal subpopulations in the mouse serves as a valuable model of epilepsy caused by mTOR hyperactivation. To better understand how gene deletions lead to altered neuronal activity, we investigated the synaptic and network effects that occur 1 week after Pten deletion. PTEN loss increased the connectivity of all four types of hippocampal synaptic connections, including two forms of increased inhibition of inhibition, and increased network functional connectivity. These data suggest that single gene mutations that cause neurological diseases such as epilepsy may affect a surprising range of connection types. Moreover, given the robustness of homeostatic plasticity, these diverse effects on connection types may be necessary to cause network phenotypes such as increased synchrony.

EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48h silencing with the Na+ channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons have lower levels of early endosome antigen 1 (EEA1), a protein involved in AMPA-type glutamate receptor endocytosis. In addition, expression of EEA1 in Mecp2 KO neurons reduced mEPSC amplitudes to wild-type levels, and restored synaptic scaling down of mEPSC amplitudes after 48h blockade of GABAA R-mediated inhibition with bicuculline. The identification of a molecular deficit in HSP in Mecp2 KO neurons provides potentially novel targets of intervention for improving hippocampal function in Rett syndrome individuals.

Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.

Myosin II activity is required for structural plasticity at the axon initial segment.

In neurons, axons possess a molecularly defined and highly organised proximal region – the axon initial segment (AIS) – that is a key regulator of both electrical excitability and cellular polarity. Despite existing as a large, dense structure with specialised cytoskeletal architecture, the AIS is surprisingly plastic, with sustained alterations in neuronal activity bringing about significant alterations to its position, length or molecular composition. However, although the upstream activity‐dependent signalling pathways that lead to such plasticity have begun to be elucidated, the downstream mechanisms that produce structural changes at the AIS are completely unknown. Here, we use dissociated cultures of rat hippocampus to show that two forms of AIS plasticity in dentate granule cells – long‐term relocation, and more rapid shortening – are completely blocked by treatment with blebbistatin, a potent and selective myosin II ATPase inhibitor. These data establish a link between myosin II and AIS function, and suggest that myosin II's primary role at the structure may be to effect activity‐dependent morphological alterations.

Prefrontal-parietal effective connectivity during working memory in older adults

Theoretical models and preceding studies have described age-related alterations in neuronal activation of frontoparietal regions in a working memory (WM) load-dependent manner. However, to date, underlying neuronal mechanisms of these WM load-dependent activation changes in aging remain poorly understood. The aim of this study was to investigate these mechanisms in terms of effective connectivity by application of dynamic causal modeling with Bayesian Model Selection. Eighteen healthy younger (age: 20–32 years) and 32 older (60–75 years) participants performed an n-back task with 3 WM load levels during functional magnetic resonance imaging (fMRI). Behavioral and conventional fMRI results replicated age group by WM load interactions. Importantly, the analysis of effective connectivity derived from dynamic causal modeling, indicated an age- and performance-related reduction in WM load-dependent modulation of connectivity from dorsolateral prefrontal cortex to inferior parietal lobule. This finding provides evidence for the proposal that age-related WM decline manifests as deficient WM load-dependent modulation of neuronal top-down control and can integrate implications from theoretical models and previous studies of functional changes in the aging brain.

Network-wide oscillations in the parkinsonian state: alterations in neuronal activities occur in the premotor cortex in parkinsonian nonhuman primates

A number of studies suggest that Parkinson's disease (PD) is associated with alterations of neuronal activity patterns in the basal-ganglia-thalamocortical circuit. There are limited electrophysiological data, however, describing how the premotor cortex, which is involved in movement and decision-making, is likely impacted in PD. In this study, spontaneous local field potential (LFP) and single unit neuronal activity were recorded in the dorsal premotor area of nonhuman primates in both the naïve and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In both animals, we observed a shift of power in LFP power spectral densities (1-350 Hz) from higher to lower frequency bands; parkinsonism resulted in increased power in frequencies <8 Hz and decreased power at frequencies >30 Hz. A comparable but not identical trend was observed in the power spectral analysis of single unit spike trains: alpha power increased in both animals and gamma power decreased in one; power in other frequency bands remaining unchanged. Although not consistent across animals, we also observed changes in discharge rates and bursting activity. Overall, the LFP and single unit analysis suggest that abnormalities in premotor neural activity are a feature of parkinsonism, although specific details of those abnormalities may differ between subjects. This study further supports the concept that PD is a network disorder that induces abnormal spontaneous neural activities across the basal-ganglia-thalamocortical circuit including the premotor cortex and provides foundational knowledge for future studies regarding the relationship between changes in neuronal activity in this region and the development of motor deficits in PD.NEW & NOTEWORTHY This study begins to fill a gap in knowledge regarding how Parkinson's disease (PD) may cause abnormal functioning of the premotor cortex. It is novel as the premotor activity is examined in both the naïve and parkinsonian states, in the same subjects, at the single unit and LFP level. It provides foundational knowledge on which to build future studies to explore the relationships between premotor activities and specific parkinsonian motor and cognitive deficits.

Age-dependent alterations in neuronal activity in the hippocampus and visual cortex in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by autosomal recessive mutations in CLN3. JNCL is typified by progressive neurodegeneration that has been suggested to occur from excessive excitatory and impaired inhibitory synaptic input; however, no studies to date have directly evaluated neuronal function. To examine changes in neuronal activity with advancing disease, electrophysiological recordings were performed in the CA1 hippocampus (HPC) and visual cortex (VC) of acute brain slices from Cln3Δex7/8 mice at 1, 4, 8, and 12months of age. Basic electrophysiological parameters, such as field excitatory post-synaptic potential (fePSP) and population spike (PS) amplitudes, were not altered in Cln3Δex7/8 CA1 and VC neurons at any age. However, fiber volley (FV) amplitudes were significantly increased in Cln3Δex7/8 neurons in the HPC at 1month as well as layer II/III of the VC at 1 and 4months, suggesting increased axonal excitability. In older Cln3Δex7/8 mice (8 and 12months), FV amplitude in the CA1 HPC and VC reached levels that were equal to or significantly lower than WT animals. Significant alterations in the synaptic strength of Cln3Δex7/8 CA1 neurons were also linked to age-dependent changes in axonal responses. Additionally, paired-pulse and 12-pulse facilitation responses calculated from PS recordings were significantly decreased in the CA1 HPC and layer II/III of the VC of Cln3Δex7/8 mice at all ages, suggesting permanent alterations in neuronal short-term plasticity. Collectively, our study has identified novel age- and region-dependent alterations in axonal excitability as well as synaptic and non-synaptic neuronal activity in Cln3Δex7/8 mice during disease progression, which may inform neurodegenerative mechanisms in JNCL.

Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex.

The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine parabrachial-Kölliker-Fuse (PB-KF) complex of dogs was identified via microinjections, in which localized pharmacologically induced increases in neuronal activity produced increases in breathing rate while decreases in neuronal activity produced decreases in breathing rate. This subregion is also very sensitive to local and systemic opioids. The purpose of this study was to precisely characterize the relationship between the PB-KF subregion pattern of altered neuronal activity and the control of respiratory phase timing as well as the time course of the phrenic nerve activity/neurogram (PNG). Pulse train electrical stimulation patterns synchronized with the onset of the expiratory (E) and/or phrenic inspiratory (I) phase were delivered via a small concentric bipolar electrode while the PNG was recorded in decerebrate, vagotomized dogs. Step frequency patterns during the E phase produced a marked frequency-dependent decrease in Te, while similar step inputs during the I phase increased inspiratory duration (Ti) by 14 ± 3%. Delayed pulse trains were capable of pacing the breathing rate by terminating the E phase and also of triggering a consistent stereotypical inspiratory PNG pattern, even when evoked during apnea. This property suggests that the I-phase pattern generator functions in a monostable circuit mode with a stable E phase and a transient I phase. Thus the I-pattern generator must contain neurons with nonlinear pacemaker-like properties, which allow the network to rapidly obtain a full on-state followed by relatively slow inactivation. The activated network can be further modulated and supplies excitatory drive to the neurons involved with pattern generation.NEW & NOTEWORTHY A circumscribed subregion of the pontine medial parabrachial nucleus plays a key role in the control of breathing frequency primarily via changes in expiratory duration. Excitation of this subregion triggers the onset of the inspiratory phase, resulting in a stereotypical ramplike phrenic activity pattern independent of time within the expiratory phase. The ability to pace the I-burst rate suggests that the in vivo I-pattern generating network must contain functioning pacemaker neurons.

Activity-dependent redistribution of Kv2.1 ion channels on rat spinal motoneurons.

Homeostatic plasticity occurs through diverse cellular and synaptic mechanisms, and extensive investigations over the preceding decade have established Kv2.1 ion channels as key homeostatic regulatory elements in several central neuronal systems. As in these cellular systems, Kv2.1 channels in spinal motoneurons (MNs) localize within large somatic membrane clusters. However, their role in regulating motoneuron activity is not fully established in vivo. We have previously demonstrated marked Kv2.1 channel redistribution in MNs following in vitro glutamate application and in vivo peripheral nerve injury (Romer et al., 2014, Brain Research, 1547:1–15). Here, we extend these findings through the novel use of a fully intact, in vivo rat preparation to show that Kv2.1 ion channels in lumbar MNs rapidly and reversibly redistribute throughout the somatic membrane following 10 min of electrophysiological sensory and/or motor nerve stimulation. These data establish that Kv2.1 channels are remarkably responsive in vivo to electrically evoked and synaptically driven action potentials in MNs, and strongly implicate motoneuron Kv2.1 channels in the rapid homeostatic response to altered neuronal activity.

Role of GABAA R trafficking in the plasticity of inhibitory synapses.

Neuronal excitability depends on the balance between inhibitory and excitatory neurotransmission, which in the CNS are mainly mediated by GABA and glutamate respectively. The plasticity of glutamatergic synapses and the underlying molecular mechanisms have been characterized to a large extent. In comparison, much less is known regarding the plasticity of GABAergic synapses, which is also important in the maintenance of the excitatory/inhibitory balance. GABAergic synapses, similarly to the glutamatergic synapses, adjust their strength depending on the pattern of neuronal activity. These alterations take place in the pre- and postsynaptic compartments, and short- and long-term alterations have been described. At the postsynaptic level the plasticity of inhibitory synapses is largely mediated by modulation of the expression, localization and function of GABAA receptors, by mechanisms involving the participation of scaffold proteins and structural molecules. This review is focused on the key mechanisms that regulate GABAA receptor trafficking in response to alterations in neuronal activity or to stimulation of plasma membrane receptors. These alterations in GABAergic neurotransmission are important in the refinement of the pattern of activity of neuronal networks. In this work, we review some of the mechanisms contributing to the plasticity of inhibitory synapses in the CNS, focusing on the regulation of GABAA receptor (GABAA R) trafficking in response to alterations in neuronal activity or to stimulation of different classes of plasma membrane-associated receptors. Alterations in these mechanisms are important in the refinement of neuronal network activity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".

Ambient Glutamate Promotes Paroxysmal Hyperactivity in Cortical Pyramidal Neurons at Amyloid Plaques via Presynaptic mGluR1 Receptors

Synaptic dysfunctions and altered neuronal activity play major role in the pathophysiology of Alzheimer's disease (AD), with underlying mechanisms largely unknown. We report that in the prefrontal cortex of amyloid precursor protein-presenilin 1 and APP23 AD mice, baseline activity of pyramidal cells is disrupted by episodes of paroxysmal hyperactivity. Induced by spontaneous EPSC bursts, these incidents are prevalent in neurons proximal to amyloid plaques and involve enhanced activity of glutamate with metabotropic effects. Abolition of EPSC bursts by tetrodotoxin and SERCA ATPase blockers thapsigargin or cyclopiasonic acid suggests their presynaptic origin and sensitized store-released calcium. Accordingly, the rate of EPSC bursts activated by single axon stimulation is enhanced. Aggravation of the hyperactivity by blockers of excitatory amino acid transporter (±)-HIP-A and DL-TBOA together with histochemical and ultrastructural evidence for enrichment of plaque-related dystrophies with synaptic vesicles and SNARE protein SNAP-25 infer the later as hot-spots for ectopic release of glutamate. Inhibition of EPSC bursts by I/II mGluR1 blocker MCPG or selective mGluR1 antagonist LY367385 implicate metabotropic glutamatergic effects in generation of paroxysmal bursts. These findings demonstrate for the first time that at amyloid plaques, enhanced activity of nonsynaptic glutamate can promote irregular EPSC bursts with hyperactivity of pyramidal cells via mGluR1 receptors.

Domoic acid disrupts the activity and connectivity of neuronal networks in organotypic brain slice cultures

Domoic acid is a neurotoxin produced by algae and is found in seafood during harmful algal blooms. As a glutamate agonist, domoic acid inappropriately stimulates excitatory activity in neurons. At high doses, this leads to seizures and brain lesions, but it is unclear how lower, asymptomatic exposures disrupt neuronal activity. Domoic acid has been detected in an increasing variety of species across a greater geographical range than ever before, making it critical to understand the potential health impacts of low-level exposure on vulnerable marine mammal and human populations. To determine whether prolonged domoic acid exposure altered neuronal activity in hippocampal networks, we used a custom-made 512 multi-electrode array with high spatial and temporal resolution to record extracellular potentials (spikes) in mouse organotypic brain slice cultures. We identified individual neurons based on spike waveform and location, and measured the activity and functional connectivity within the neuronal networks of brain slice cultures. Domoic acid exposure significantly altered neuronal spiking activity patterns, and increased functional connectivity within exposed cultures, in the absence of overt cellular or neuronal toxicity. While the overall spiking activity of neurons in domoic acid-exposed cultures was comparable to controls, exposed neurons spiked significantly more often in bursts. We also identified a subset of neurons that were electrophysiologically silenced in exposed cultures, and putatively identified those neurons as fast-spiking inhibitory neurons. These results provide evidence that domoic acid affects neuronal activity in the absence of cytotoxicity, and suggest that neurodevelopmental exposure to domoic acid may alter neurological function in the absence of clinical symptoms.

EP 50. High frequency stimulation of the rat dorsal cochlear nucleus inhibits tinnitus

Introduction Tinnitus can cause a serious burden on patients and remains often treatment-resistant. Up to date no standard effective treatment is available. Deep brain stimulation (DBS) has been widely applied for various neurological disorders, most often in patients with Parkinson’s disease. There is growing evidence that deep brain stimulation might be able to interrupt the local altered neuronal activity found in tinnitus and hereby inhibit tinnitus perception. Multiple preclinical and clinical studies suggest that the dorsal cochlear nucleus (DCN) plays an important role in the development of tinnitus and could therefore be a target for DBS in tinnitus. We hypothesized that tinnitus can be treated with high-frequency DBS of the DCN. Objectives In this study we assessed treatment of experimental tinnitus with high-frequency and low-frequency DBS in the DCN in an animal model with behavioral signs of tinnitus in an intra-individual controlled experimental design. Materials and methods In ten Sprague Dawley rats the startle reflex using the pre-pulse inhibition (PPI) paradigm was measured as a pretest. Tinnitus was defined as an increase in the gap/no-gap ratio. After bilateral DBS implantation in the DCN the sham situation was assessed including screening of hearing using the auditory brainstem response (ABR). Unilateral tinnitus was induced using a 16 kHz octave-banded noise and the PPI and ABR were again measured. The effect of high-frequency (100 Hz, 60 ms pulse with, 100 mA) and low-frequency (10 Hz, 60 ms pulse with, 100 mA) DBS of the DCN on tinnitus was assessed after noise trauma. Results Histological examination showed that the electrodes were correctly positioned within the DCN. After noise trauma the gap/no-gap ratio was increased at 16 and 20 kHz ( p p Conclusion This study shows that high-frequency DBS of the DCN is effective in reducing experimental tinnitus in a validated animal model. Optimal parameters for stimulation and side effects should be further investigated. It is worthwhile to investigate the effect of DBS in other more accessible brain structures within the auditory pathway for human application.

Neuromodulation for Post-Stroke Aphasia

Aphasia is a prominent sequela of stroke that affects the language centres and negatively impacts the quality of daily living of stroke survivors. Speech and language therapy (SLT) still stands as the only therapy modality with robust evidence, but in the past three decades, many studies have reported the potential utility of neuromodulation to enhance the effects of SLT. Through the application of either non-invasive or invasive magnetic or electrical stimulation or neuro-active pharmaceutical agents, neuromodulation induces alteration of neuronal activity. In this paper, we provide a focused review of key studies investigating the use of neuromodulation techniques, namely transcranial magnetic and direct current stimulation, to map speech and language function and enhance speech recovery after stroke. Neuromodulation, on its own or combined with other modalities, such as pharmacotherapy or SLT, holds a lot of promise in the management of aphasia. Neuromodulation treatment protocols need to be better understood and optimized and validated by adequately powered, randomized, double-blind clinical trials.

Molecular Features Underlying Neurodegeneration Identified through InVitro Modeling of Genetically Diverse Parkinson's Disease Patients.

The fact that Parkinson's disease (PD) can arise fromnumerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. To address this hypothesis, wetook an integrated approach utilizing invitro disease modeling and comprehensive transcriptome profiling to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions.To model PD invitro, we generated neurons harboring disease-causing mutations from patient-specific, induced pluripotent stem cells (iPSCs). We observed signs of degeneration in midbrain dopaminergic neurons, reflecting the cardinal feature of PD.Gene expression signatures of PD neurons provided molecular insights into disease phenotypes observed invitro, including oxidative stress vulnerability and altered neuronal activity. Notably, PD neurons show that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, underlies apattern of alternative RNA-processing associated with PD-specific phenotypes.