For probe trials, the platform was removed and each mouse was allowed to swim for 60 sec. After obtaining the primary hTau mouse embryonic forebrain neuronal cultures expressing a human MAPT gene, the cultures were treated with oligomers to inhibit the Tau mRNA and protein expression. Exemplary methods of preparing such oligomers are described in Barciszewski et al., Chapter 10-"Locked Nucleic Acid Aptamers" in Nucleic Acid and Peptide Aptamers: Methods and Protocols, vol. A number of molecules (e.g., oligomers) are designed to target the 3' UTR of MAPT pre-mRNA. The oligomers were synthesized using methods well known in the art. All of the references cited above, as well as all references cited herein, are incorporated herein by reference in their entireties. And we hope to help you ignite your imagination and perhaps explore new tastes and fantasies as well. Therapeutic proteins that reduce calcium oscillations to levels below 70% of control will be expected to negatively impact CNS network activity in vivo and electrophysiologic spontaneous neuronal activity in vitro.



Small molecules that reduce calcium oscillations to levels below 70% of control will be expected to negatively impact CNS network activity in vivo and electrophysiologic spontaneous neuronal activity in vitro. Addition of small molecule will inhibit AMPA receptor mediated oscillations. Small molecule inhibition of spontaneous calcium oscillations mediated by either NMDA or AMPA will be assessed. Spatial learning and memory was assessed based on Morris Water Maze assay (Morris J. Neurosci. Water maze represents a pool with the diameter of 120 cm. Prior to hidden platform training, all mice were exposed to the water maze pool by allowing them to swim down the rectangular channel during 2 pre-training trials. Escape latencies, distance traveled, swim paths, swim speeds, and platform crossings were recorded automatically for subsequent analysis. The escape platform was placed in the middle of the channel. 2 h following the 16 h probe trial, all mice underwent the visible platform training, where a local cue (pole built using legos) was placed above the hidden platform. For MWM, a repeated MWM ANOVA was used to analyze the acquisition phase and a one-way ANOVA followed by Dunnett's post-hoc for probe trial analyses.



For NOR, data were analyzed using either a paired t-test for within-group analyses or by an ANOVA followed by a Dunnett's post-hoc test for between group analyses. Statistical analyses for all behavioral tests were conducted using GraphPad Prism (GraphPad Software, Inc., La Jolla, Calif.). Behavioral studies were conducted between 0700 and 1500 hours. The sequence score of the selected oligomers were calculated for further studies. Effect of oligomers on primary neuronal spontaneous calcium oscillations was measured under two conditions, in the presence and absence of 1 mM MgCl2 as described previously (Murphy et. Addition of therapeutic protein will inhibit AMPA receptor mediated oscillations. Calcium oscillation reduction in the neuronal cells was measured for the oligomers of the invention and compared with that of the control cells (i.e., the calcium oscillations in the neuronal cells that are not treated with the oligomers). 4, 5, and 6. In some embodiments, the oligomers were designed to be gapmers or mixmers. The in vivo tolerability of the oligomers was tested to see how the oligomer was tolerated when injected into an animal.



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