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Prescott S.A.,Neurosciences and Mental Health | Prescott S.A.,University of Toronto
Progress in Molecular Biology and Translational Science | Year: 2015

Nociceptive signals originating in the periphery must be transmitted to the brain to evoke pain. Rather than being conveyed unchanged, those signals undergo extensive processing in the spinal dorsal horn. Synaptic inhibition plays a crucial role in that processing. On the one hand, neuropathy and inflammation are associated with reduced spinal inhibition; on the other hand, the hypersensitivity associated with inflammatory and neuropathic pain can be reproduced by blocking inhibition at the spinal level. To understand the consequences of disinhibition and how to therapeutically reverse it, one must understand how synaptic inhibition normally operates. To that end, this chapter will discuss the structure and function of GABAA and glycine receptors together with the role of associated molecules involved in transmitter handling and chloride regulation. Mechanisms by which inhibition modulates cellular excitability will be described. The chapter will end with discussion of how inhibition goes awry under pathological conditions and what the implications are for the treatment of resulting pain. © 2015 Elsevier Inc.


Ehrlich D.E.,NYU Langone Medical Center | Ehrlich D.E.,New York University | Josselyn S.A.,Neurosciences and Mental Health | Josselyn S.A.,University of Toronto
Genes, Brain and Behavior | Year: 2016

Learning about motivationally important stimuli involves plasticity in the amygdala, a temporal lobe structure. Amygdala-dependent learning involves a growing number of plasticity-related signaling pathways also implicated in brain development, suggesting that learning-related signaling in juveniles may simultaneously influence development. Here, we review the pleiotropic functions in nervous system development and amygdala-dependent learning of a signaling pathway that includes brain-derived neurotrophic factor (BDNF), extracellular signaling-related kinases (ERKs) and cyclic AMP-response element binding protein (CREB). Using these canonical, plasticity-related genes as an example, we discuss the intersection of learning-related and developmental plasticity in the immature amygdala, when aversive and appetitive learning may influence the developmental trajectory of amygdala function. We propose that learning-dependent activation of BDNF, ERK and CREB signaling in the immature amygdala exaggerates and accelerates neural development, promoting amygdala excitability and environmental sensitivity later in life. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.


Sinopoli K.J.,Physiology and Experimental Medicine | Sinopoli K.J.,University of Toronto | Schachar R.,Neurosciences and Mental Health | Schachar R.,University of Toronto | And 2 more authors.
Journal of Clinical and Experimental Neuropsychology | Year: 2011

Poor inhibitory control and abnormalities in responding to rewards are characteristic of the developmental or primary form of attention-deficit/ hyperactivity disorder (P-ADHD). A secondary form of ADHD (S-ADHD) may occur as a consequence of childhood traumatic brain injury (TBI), but the similarities and differences between these two forms of ADHD have not been well characterized. To address these issues, we studied two inhibitory control tasks under different reward conditions in four groups of children and adolescents: TBI who did not exhibit S-ADHD, TBI who did exhibit S-ADHD, P-ADHD, and healthy controls. Participants with TBI exhibited poor cancellation inhibition relative to controls. Although reward facilitated both cancellation and restraint inhibition similarly across groups, poor performance persisted in the P-ADHD group, and participants with S-ADHD exhibited a selective deficit in cancellation inhibition. © 2011 Psychology Press.


Asrar S.,Neurosciences and Mental Health | Asrar S.,University of Toronto | Jia Z.,Neurosciences and Mental Health | Jia Z.,University of Toronto | Jia Z.,Nanjing Southeast University
Cellular Signalling | Year: 2013

Long-lasting synaptic plasticity involves changes in both synaptic morphology and electrical signaling (here referred to as structural and functional plasticity). Recent studies have revealed a myriad of molecules and signaling processes that are critical for each of these two forms of plasticity, but whether and how they are mechanistically linked to achieve coordinated changes remain controversial.It is well accepted that functional plasticity at the excitatory synapse is dependent upon the activities of glutamate receptors. While the activation of NMDARs (N-methyl-D-aspartic acid receptors) and/or mGluRs (metabotropic glutamate receptors) is required for the induction of many forms of plasticity, AMPARs (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors), the principal mediators of fast excitatory synaptic transmission, are the ultimate targets of modifications that express functional plasticity. Investigations exploring structural plasticity have been mainly focused on the small membranous protrusions on the dendrites called spines. The morphological regulation of these spines is mediated by the reorganization of the actin cytoskeleton, the predominant structural component of the synapse. In this regard, the Rho family of GTPases, particularly Rac1, RhoA and Cdc42, is found to be the central regulator of spine actin and structural plasticity of the synapse.It is thought that the collaborative interaction between functional and structural factors underlies the sustained or permanent nature of long-lasting synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), the most extensively studied forms of synaptic plasticity widely regarded as cellular mechanisms for learning and memory. However, data specifically pertaining to whether and how these two distinct components are linked at the molecular level remain sparse. In this regard, we have identified a number of synaptic proteins that are involved in both structural and functional changes during mGluR-dependent LTD (mGluR-LTD). Among these are the GluA2 (formerly called GluR2) subunit of AMPARs, Rac1 and Rac1-activated kinases. We have discovered that these proteins interact and reciprocally regulate each other, which led us to hypothesize that the GluA2-Rac1 interaction may serve as a coordinator between functional and morphological plasticity. In this review, we will briefly discuss the available evidence to support such a hypothesis. © 2012 Elsevier Inc.


Lipszyc J.,Neurosciences and Mental Health | Lipszyc J.,University of Toronto | Schachar R.,Neurosciences and Mental Health | Schachar R.,University of Toronto
Journal of the International Neuropsychological Society | Year: 2010

The Stop Signal Task (SST) is a measure that has been used widely to assess response inhibition. We conducted a meta-analysis of studies that examined SST performance in patients with various psychiatric disorders to determine the magnitude and generality of deficient inhibition. A five-item instrument was used to assess the methodological quality of studies. We found medium deficits in stop signal reaction time (SSRT), reflecting the speed of the inhibitory process, for attention-deficit hyperactivity disorder (ADHD) (g = 0.62), obsessive compulsive disorder (OCD) (g = 0.77) and schizophrenia (SCZ) (g = 0.69). SSRT was less impaired or normal for anxiety disorder (ANX), autism, major depressive disorder (MDD), oppositional defiant disorder/conduct disorder (ODD/CD), pathological gambling, reading disability (RD), substance dependence, and Tourette syndrome. We observed a large SSRT deficit for comorbid ADHD + RD (g = 0.82). SSRT was less than moderately impaired for ADHD + ANX and ADHD + ODD/CD. Study quality did not significantly affect SSRT across ADHD studies. This confirms an inhibition deficit in ADHD, and suggests that comorbid ADHD has different effects on inhibition in patients with ANX, ODD/CD, and RD. Further studies are needed to firmly establish an inhibition deficit in OCD and SCZ. (JINS, 2010, 16, 1064-1076.) Copyright © The International Neuropsychological Society 2010.

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