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PubMed | McGill University, Hospital for Sick Children Research Institute Toronto, York University, University of Toronto and 2 more.
Type: | Journal: Frontiers in cellular neuroscience | Year: 2015

Neto2 is a transmembrane protein that interacts with the neuron-specific K(+)-Cl(-) cotransporter (KCC2) in the central nervous system (CNS). Efficient KCC2 transport is essential for setting the neuronal Cl(-) gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter. In the present study, we characterized GABAergic inhibition and KCC2-mediated neuronal chloride homeostasis in pyramidal neurons from adult hippocampal slices. Using gramicidin perforated patch clamp recordings we found that the reversal potential for GABA (EGABA) was significantly depolarized. We also observed that surface levels of KCC2 and phosphorylation of KCC2 serine 940 (Ser940) were reduced in Neto2(-/-) neurons compared to wild-type controls. To examine GABAergic inhibition we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) and found that Neto2(-/-) neurons had significant reductions in both their amplitude and frequency. Based on the critical role of Neto2 in regulating GABAergic inhibition we rationalized that Neto2-null mice would be prone to seizure activity. We found that Neto2-null mice demonstrated a decrease in the latency to pentylenetetrazole (PTZ)-induced seizures and an increase in seizure severity.

PubMed | University of Toronto, Hospital for Sick Children Research Institute Toronto and University of TorontoToronto
Type: | Journal: Frontiers in human neuroscience | Year: 2016

Adults who stutter (AWS) have demonstrated atypical coordination of motor and sensory regions during speech production. Yet little is known of the speech-motor network in AWS in the brief time window preceding audible speech onset. The purpose of the current study was to characterize neural oscillations in the speech-motor network during preparation for and execution of overt speech production in AWS using magnetoencephalography (MEG). Twelve AWS and 12 age-matched controls were presented with 220 words, each word embedded in a carrier phrase. Controls were presented with the same word list as their matched AWS participant. Neural oscillatory activity was localized using minimum-variance beamforming during two time periods of interest: speech preparation (prior to speech onset) and speech execution (following speech onset). Compared to controls, AWS showed stronger beta (15-25 Hz) suppression in the speech preparation stage, followed by stronger beta synchronization in the bilateral mouth motor cortex. AWS also recruited the right mouth motor cortex significantly earlier in the speech preparation stage compared to controls. Exaggerated motor preparation is discussed in the context of reduced coordination in the speech-motor network of AWS. It is further proposed that exaggerated beta synchronization may reflect a more strongly inhibited motor system that requires a stronger beta suppression to disengage prior to speech initiation. These novel findings highlight critical differences in the speech-motor network of AWS that occur prior to speech onset and emphasize the need to investigate further the speech-motor assembly in the stuttering population.

PubMed | Hospital for Sick Children Research Institute Toronto
Type: | Journal: Frontiers in human neuroscience | Year: 2013

The human motor cortex exhibits transient bursts of high frequency gamma oscillations in the 60-90 Hz range during movement. It has been proposed that gamma oscillations generally reflect local intracortical activity. However, movement-evoked gamma is observed simultaneously in both cortical and subcortical (basal ganglia) structures and thus appears to reflect long-range cortical-subcortical interactions. Recent evidence suggests that gamma oscillations do not simply reflect sensory reafference, but have a facilitative role in movement initiation. Here we summarize contributions of MEG to our understanding of movement-evoked gamma oscillations, including evidence that transient gamma bursts during the performance of specific movements constitutes a stereotyped spectral and temporal pattern within individuals-a gamma fingerprint-that is highly stable over time. Although their functional significance remains to be fully understood, movement-evoked gamma oscillations may represent frequency specific tuning within cortical-subcortical networks that can be monitored non-invasively using MEG during a variety of motor tasks, and may provide important information regarding cortical dynamics of ongoing motor control.

PubMed | Hospital for Sick Children Research Institute Toronto
Type: | Journal: Frontiers in human neuroscience | Year: 2012

Human action involves a combination of controlled and automatic behavior. These processes may interact in tasks requiring rapid response selection or inhibition, where temporal constraints preclude timely intervention by conscious, controlled processes over automatized prepotent responses. Such contexts tend to produce frequent errors, but also rapidly executed correct responses, both of which may sometimes be perceived as surprising, unintended, or automatic. In order to identify neural processes underlying these two aspects of cognitive control, we measured neuromagnetic brain activity in 12 right-handed subjects during manual responses to rapidly presented digits, with an infrequent target digit that required switching response hand (bimanual task) or response finger (unimanual task). Automaticity of responding was evidenced by response speeding (shorter response times) prior to both failed and fast correct switches. Consistent with this automaticity interpretation of fast correct switches, we observed bilateral motor preparation, as indexed by suppression of beta band (15-30 Hz) oscillations in motor cortex, prior to processing of the switch cue in the bimanual task. In contrast, right frontal theta activity (4-8 Hz) accompanying correct switch responses began after cue onset, suggesting that it reflected controlled inhibition of the default response. Further, this activity was reduced on fast correct switch trials suggesting a more automatic mode of inhibitory control. We also observed post-movement (event-related negativity) ERN-like responses and theta band increases in medial and anterior frontal regions that were significantly larger on error trials, and may reflect a combination of error and delayed inhibitory signals. We conclude that both automatic and controlled processes are engaged in parallel during rapid motor tasks, and that the relative strength and timing of these processes may underlie both optimal task performance and subjective experiences of automaticity or control.

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