Two forms of evoked neurotransmitter release at excitatory synapses between cultured hippocampal neurons have been described. After an action potential, it has been shown that transmitter initially is released synchronously, and this is followed by a period of "slow" asynchronous release. The "fast" synchronous component of release at these synapses has been found routinely to demonstrate paired-pulse and tetanic depression, whereas the short-term plasticity of asynchronous release has not been investigated. In the present experiments, we have used the whole-cell patch-clamp technique to record from pairs of neurons in a low-density hippocampal culture preparation to determine both the properties and underlying mechanisms of short-term plasticity of asynchronous release. It was found that an increase in miniature EPSC (mEPSC) frequency accompanied both single and multiple stimuli, and this mEPSC increase was facilitated during paired stimuli, even when the evoked synchronous release was depressed. In addition, both the activity-dependent depression of evoked EPSCs and facilitation of asynchronous mEPSC release were dependent on Ca accumulation in the nerve terminal. However, the Ca-dependent mechanisms underlying these two processes could be distinguished by the differential effects of two membrane-permeant calcium chelators, BAPTA-AM and EGTA-AM. Frequency-dependent depression of evoked EPSCs involves a rapid rise in intraterminal Ca, which likely triggers a process that proceeds in a Ca-independent manner, whereas the asynchronous release may be linked more directly to a sustained increase in intraterminal Ca. Key words: mEPSC; synaptic plasticity; BAPTA-AM; EGTA-AM; hippocampal culture; paired-pulse facilitation; paired-pulse depressionA two-component model of CNS excitatory neurotransmitter release has been proposed on the basis of recent experiments at excitatory synapses in hippocampal neuronal cultures (Geppert et al., 1994;Goda and Stevens, 1994). According to this model, action potentials result in an initial "fast" synchronous release of transmitter that is accompanied by a period of "slow" asynchronous release. The fast synchronous release produces a large evoked EPSC, whereas the asynchronous release is manifested by the appearance of small, miniature EPSCs (mEPSCs) that persist for up to 500 msec after the evoked EPSC. These two components are differentially sensitive to divalent cations, such that substitution of Sr 2ϩ for Ca 2ϩ can eliminate synchronous release, whereas asynchronous release is unaffected . In addition, cultured hippocampal neurons obtained from "knockout" mice lacking synaptotagmin I retain only the asynchronous form of neurotransmitter release (Geppert et al., 1994). The short-term plasticity of the fast synchronous component of neurotransmitter release at hippocampal synapses has been examined both in culture (Forsythe and Clements, 1990;Mennerick and Zorumski, 1995) and slice preparations (Creager et al., 1980;McNaughton, 1980;Griffith, 1990;Stevens and Wang, 1995). However, to...

The objective of this study was to evaluate the neuropsychiatric effects of the alpha-2a adrenergic agonist guanfacine in children with Tourette syndrome (TS). Twenty-four children with TS participated in a 4-week, double-blind, placebo-controlled study of guanfacine. Tic severity, neuropsychologic functioning, and parent ratings of behavior were evaluated pre- and post-treatment. The sample had mild tic severity and subtle neuropsychologic dysfunction pretreatment. Post-treatment, patients receiving guanfacine were rated by parents as significantly improved (compared to placebo) on one measure of executive function (parent-rated metacognition). Improvement on tic severity, performance-based neuropsychologic measures, and all other parent ratings were not significantly better than placebo. At a moderate dose and short-term treatment duration, guanfacine did not provide significant neuropsychiatric benefits in this group of children with mild TS.

BACKGROUND AND PURPOSE In adult stroke, the advent of thrombolytic therapy led to the development of Primary Stroke Centers able to diagnose and treat patients with acute stroke rapidly. We describe the development of Primary Pediatric Stroke Centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) Trial. METHODS We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate and treat pediatric stroke rapidly, including use of thrombolytic therapy. RESULTS Prior to 2004 <25% of TIPS sites had continuous twenty-four hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. Following TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1–10 Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 prior to site preparation to 8.7 at the time of site activation (P=<0.001). CONCLUSIONS Prior to preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tPA.