Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are the most widely studied forms of synaptic plasticity thought to underlie spatial learning and memory. We report here that RARbeta deficiency in mice virtually eliminates hippocampal CA1 LTP and LTD. It also results in substantial performance deficits in spatial learning and memory tasks. Surprisingly, RXRgamma null mice exhibit a distinct phenotype in which LTD is lost whereas LTP is normal. Thus, while retinoid receptors contribute to both LTP and LTD, they do so in different ways. These findings not only genetically uncouple LTP and LTD but also reveal a novel and unexpected role for vitamin A in higher cognitive functions.

Cannabinoids, the active constituents of marijuana, are known to impair learning and memory. Receptors for cannabinoids are highly expressed in the hippocampus, a brain region that is believed to play an important role in certain forms of learning and memory. To investigate the possible contribution of cannabinoid receptor-mediated deficits in hippocampal function to the learning and memory impairments produced by marijuana, we studied the effects of cannabinoid receptor activation on two models of learning and memory, long-term potentiation (LTP) and long-term depression (LTD), in hippocampal slices. Although LTP and LTD of CA1 field potentials were blocked by cannabinoid receptor activation in the presence of Mg(2+), they could be induced after Mg(2+) was removed. Similarly, LTP and LTD of whole-cell EPSCs were unimpaired in the presence of cannabinoid receptor agonist when the postsynaptic membrane was depolarized during the LTP or LTD induction protocol. Cannabinoid receptor activation also reduced EPSCs and enhanced paired-pulse facilitation, while having no effect on the amplitude of spontaneous miniature EPSCs. Finally, as with cannabinoid receptor activation, inhibition of LTP by adenosine receptor activation could be overcome by removal of Mg(2+) or depolarization of the postsynaptic membrane during tetanus. Our results indicate that cannabinoid receptor activation does not directly inhibit the molecular mechanisms responsible for long-term synaptic plasticity but instead impairs LTP and LTD by reducing presynaptic neurotransmitter release to a level below that required to depolarize the postsynaptic membrane to relieve Mg(2+) blockade of NMDA receptors.

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Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.