Tau ablation, knockdown, and reconstitution studies in primary mouse neurons show that tau enables amyloid β oligomers to inhibit axonal transport through activation of GSK3β and through functions of tau that do not depend on its microtubule binding activity.

Rationale Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic “crash”. Objective To determine whether individual differences in the relative value of cocaine’s positive and negative effects would account for variations in subsequent drug self-administration. Methods The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0 mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15 min post-injection) and a runway test (where animals developed approach-avoidance “retreat” behaviors about entering a goal-box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration. Results a) larger place preferences were associated with faster runway start latencies (rs=−0.64), but not with retreat frequency or run times; b) larger place aversions predicted slower runway start times (rs=0.62) and increased run times (rs=0.65) and retreats (rs=0.62); c) response escalation was observed in both the 1-h and 6-h self-administration groups and was associated with increased CPPs (rs=0.58) but not CPAs, as well as with faster run times (rs=−0.60). Conclusions Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.

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BackgroundPatients with Alzheimer's disease (AD) are at risk for seizures and accelerated cognitive decline. Mechanisms of seizures and related synaptic dysfunction in AD are active areas of investigation. Alterations in ion channels have been identified in transgenic mouse models of AD, but levels of voltage‐gated potassium channels (VGKCs) have not been fully explored. In particular, little is known about Kv1.1 channels in AD. Mutations in Kv1.1 or autoantibodies against Kv1.1 cause neuronal overexcitation in several human diseases, including episodic ataxia type 1, epilepsy, myokymia, and limbic encephalitis, indicating that Kv1.1 is critical for regulating neuronal excitability.MethodTo explore VGKCs in AD, we used hAPP‐J20 mice ages 4‐6 months and determined mRNA and protein levels of four highly expressed VGKCs ‐ Kv1.1, Kv1.2, Kv1.4, and Kv4.2 ‐ in dentate gyrus, entorhinal cortex, motor cortex, and somatosensory cortex (SSC).ResultUsing RT‐qPCR, we identified reductions in Kv1.1 mRNA in the SSC of hAPP‐J20 mice. Western blotting revealed reductions in the Kv1.1 channel in the SSC of hAPP‐J20 mice and human parietal cortex in mild and moderate stages of AD. Immunolabeling revealed that the reductions in Kv1.1 channels in the SSC occurred in pyramidal cells and GABAergic interneurons. Kv1.1 levels in the SSC were lower in hAPP‐J20 mice, which overexpress mutant hAPP and have high Aβ(1‐42) levels, than in the wild‐type hAPP line I5, suggesting some dependence on Aβ(1‐42) levels. Levetiracetam treatment (75 mg/kg/day) administered for 28 days did not affect Kv1.1 levels in hAPP‐J20 mice. To assess Kv1.1 depletion in an AD model, we crossed Kv1.1 heterozygous mice (Kv1.1 +/‐) with hAPP‐J9 mice, which have lower expression of mutant hAPP than J20 mice. We performed behavioral tests on mice ages 4‐9 months. While Kv1.1 +/‐ mice and hAPP‐J9 mice had normal survival, the double mutant (Kv1.1 +/‐ hAPP‐J9) mice had premature mortality and impairments in elevated plus maze and light‐dark box tests (n=16‐25 mice/genotype) of anxiety.ConclusionThese data indicate that elevated Aβ(1‐42) levels may act synergistically with Kv1.1 depletion to exacerbate cognitive deterioration in AD. Ongoing investigation will further characterize the relationships between Kv1.1 loss and AD‐related hyperexcitability.