Shisa proteins and AMPA-receptor function

Mansvelder, H.D. [Promotor]Smit, A.B. [Promotor

t1 signal measurements in pediatric brain findings after multiple exposures to gadobenate dimeglumine for imaging of nonneurologic disease

BACKGROUND AND PURPOSE: Signal intensity increases possibly suggestive of gadolinium retention have recently been reported on unenhanced T1-weighted images of the pediatric brain following multiple exposures to gadolinium-based MR contrast agents. Our aim was to determine whether T1 signal changes suggestive of gadolinium deposition occur in the brains of pediatric nonneurologic patients after multiple exposures to gadobenate dimeglumine. MATERIALS AND METHODS: Thirty-four nonneurologic patients (group 1; 17 males/17 females; mean age, 7.18 years) who received between 5 and 15 injections (mean, 7.8 injections) of 0.05 mmol/kg of gadobenate during a mean of 2.24 years were compared with 24 control patients (group 2; 16 males/8 females; mean age, 8.78 years) who had never received gadolinium-based contrast agents. Exposure to gadobenate was for diagnosis and therapy monitoring. Five blinded readers independently determined the signal intensity at ROIs in the dentate nucleus, globus pallidus, pons, and thalamus on unenhanced T1-weighted spin-echo images from both groups. Unpaired t tests were used to compare signal-intensity values and dentate nucleus–pons and globus pallidus–thalamus signal-intensity ratios between groups 1 and 2. RESULTS: Mean signal-intensity values in the dentate nucleus, globus pallidus, pons, and thalamus of gadobenate-exposed patients ranged from 366.4 to 389.2, 360.5 to 392.9, 370.5 to 374.9, and 356.9 to 371.0, respectively. Corresponding values in gadolinium-based contrast agent–naive subjects were not significantly different ( P > .05). Similarly, no significant differences were noted by any reader for comparisons of the dentate nucleus–pons signal-intensity ratios. One reader noted a difference in the mean globus pallidus–thalamus signal-intensity ratios (1.06 ± 0.006 versus 1.02 ± 0.009, P = .002), but this reflected nonsignificantly higher T1 signal in the thalamus of control subjects. The number of exposures and the interval between the first and last exposures did not influence signal-intensity values. CONCLUSIONS: Signal-intensity increases potentially indicative of gadolinium deposition are not seen in pediatric nonneurologic patients after multiple exposures to low-dose gadobenate

Comparison of retrospectively self-gated and prospectively triggered flash sequences for cine imaging of the aorta in mice at 9.4 tesla

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T1 Signal Measurements in Pediatric Brain: Findings after Multiple Exposures to Gadobenate Dimeglumine for Imaging of Nonneurologic Disease.

BACKGROUND AND PURPOSE: Signal intensity increases possibly suggestive of gadolinium retention have recently been reported on unenhanced T1-weighted images of the pediatric brain following multiple exposures to gadolinium-based MR contrast agents. Our aim was to determine whether T1 signal changes suggestive of gadolinium deposition occur in the brains of pediatric nonneurologic patients after multiple exposures to gadobenate dimeglumine. MATERIALS AND METHODS: Thirty-four nonneurologic patients (group 1; 17 males/17 females; mean age, 7.18 years) who received between 5 and 15 injections (mean, 7.8 injections) of 0.05 mmol/kg of gadobenate during a mean of 2.24 years were compared with 24 control patients (group 2; 16 males/8 females; mean age, 8.78 years) who had never received gadolinium-based contrast agents. Exposure to gadobenate was for diagnosis and therapy monitoring. Five blinded readers independently determined the signal intensity at ROIs in the dentate nucleus, globus pallidus, pons, and thalamus on unenhanced T1-weighted spin-echo images from both groups. Unpaired t tests were used to compare signal-intensity values and dentate nucleus-pons and globus pallidus-thalamus signal-intensity ratios between groups 1 and 2. RESULTS: Mean signal-intensity values in the dentate nucleus, globus pallidus, pons, and thalamus of gadobenate-exposed patients ranged from 366.4 to 389.2, 360.5 to 392.9, 370.5 to 374.9, and 356.9 to 371.0, respectively. Corresponding values in gadolinium-based contrast agent-na\uefve subjects were not significantly different (P > .05). Similarly, no significant differences were noted by any reader for comparisons of the dentate nucleus-pons signal-intensity ratios. One reader noted a difference in the mean globus pallidus-thalamus signal-intensity ratios (1.06 \ub1 0.006 versus 1.02 \ub1 0.009, P = .002), but this reflected nonsignificantly higher T1 signal in the thalamus of control subjects. The number of exposures and the interval between the first and last exposures did not influence signal-intensity values. CONCLUSIONS: Signal-intensity increases potentially indicative of gadolinium deposition are not seen in pediatric nonneurologic patients after multiple exposures to low-dose gadobenate

Mechanisms underlying the rules for associative plasticity at adult human neocortical synapses

The neocortex in our brain stores long-term memories by changing the strength of connections between neurons. To date, the rules and mechanisms that govern activity-induced synaptic changes at human cortical synapses are poorly understood and have not been studied directly at a cellular level. Here, we made whole-cell recordings of human pyramidal neurons in slices of brain tissue resected during neurosurgery to investigate spike timing-dependent synaptic plasticity in the adult human neocortex. We find that human cortical synapses can undergo bidirectional modifications in strength throughout adulthood. Both long-term potentiation and long-term depression of synapses was dependent on postsynaptic NMDA receptors. Interestingly, we find that human cortical synapses can associate presynaptic and postsynaptic events in a wide temporal window, and that rules for synaptic plasticity in human neocortex are reversed compared with what is generally found in the rodent brain. We show this is caused by dendritic L-type voltage-gated Ca2+ channels that are prominently activated during action potential firing. Activation of these channels determines whether human synapses strengthen or weaken. These findings provide a synaptic basis for the timing rules observed in human sensory and motor plasticity in vivo, and offer insights into the physiological role of L-type voltage-gated Ca2+ channels in the human brain

Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity.

Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission