Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis

Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl− load on a fast time scale, whereas Cl−extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl− gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABAAR-mediated inhibition, but increasing GABAAR input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl−. Furthermore, if spiking persisted despite the presence of GABAAR input, Cl− accumulation became accelerated because of the large Cl− driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl− and pH regulation. Several model predictions were tested and confirmed by [Cl−]i imaging experiments. Our study has thus uncovered how Cl− regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K− accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention

Comparison of bandwidths in the inferior colliculus and the auditory nerve. II: Measurement using a temporally manipulated stimulus

To localize low-frequency sounds, humans rely on an interaural comparison of the temporally encoded sound waveform after peripheral filtering. This process can be compared with cross-correlation. For a broadband stimulus, after filtering, the correlation function has a damped oscillatory shape where the periodicity reflects the filter's center frequency and the damping reflects the bandwidth (BW). The physiological equivalent of the correlation function is the noise delay (ND) function, which is obtained from binaural cells by measuring response rate to broadband noise with varying interaural time delays (ITDs). For monaural neurons, delay functions are obtained by counting coincidences for varying delays across spike trains obtained to the same stimulus. Previously, we showed that BWs in monaural and binaural neurons were similar. However, earlier work showed that the damping of delay functions differs significantly between these two populations. Here, we address this paradox by looking at the role of sensitivity to changes in interaural correlation. We measured delay and correlation functions in the cat inferior colliculus (IC) and auditory nerve (AN). We find that, at a population level, AN and IC neurons with similar characteristic frequencies (CF) and BWs can have different responses to changes in correlation. Notably, binaural neurons often show compression, which is not found in the AN and which makes the shape of delay functions more invariant with CF at the level of the IC than at the AN. We conclude that binaural sensitivity is more dependent on correlation sensitivity than has hitherto been appreciated and that the mechanisms underlying correlation sensitivity should be addressed in future studies

Macrosomatognosia in frontal lobe infarct-a case report

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Reduplicative Paramnesia: A Review

BACKGROUND: Reduplicative paramnesia (RP) is a content-specific delusional misidentification syndrome (DMS) which has received little attention in the research literature relative to other DMS. RP is thought to result from an organic rather than psychiatric cause distinguishing it from other DMS. Our systematic review examines the research literature investigating the prevalence, symptomatology and potential neurologic mechanisms underlying RP.SAMPLING AND METHODS: MEDLINE, PsycINFO, and the Cochrane Library were searched (from 1966 to February 10, 2012) with the reference lists of relevant articles examined. Case reports, clinical studies and post-mortem studies focusing on, or referring to, RP were included.RESULTS: There is a paucity of literature regarding the potential mechanisms underlying the psychological, cognitive and neurological aspects of RP. The available literature is limited by the lack of systematic clinical studies and in vivo investigations with current findings remaining only speculative. However, there does appear to be a consensus that RP may have a neurologic rather than psychiatric cause and that right and bifrontal lesions as well as the cognitive dissonance associated with memory, visuospatial and impaired conceptual integration are common factors in RP presentation.CONCLUSIONS: This area requires further extensive systematic research with supplementary in vivo data. Current studies suggest that focal lesions within the frontal lobe may account for the onset of RP.</p