Cellular/Molecular
Synaptic Activity Triggers Degradation of Arc mRNA
Shannon Farris, Gail Lewandowski, Conor D. Cox, and Oswald Steward
(see pages 4481–4493)
Long-term potentiation (LTP) of synaptic strength requires protein synthesis, and many proteins that are upregulated by synaptic activity have been identified. But evidence is accumulating that regulated degradation of protein and mRNA also has essential roles in synaptic plasticity. Among proteins upregulated by neuronal activity, the activity-regulated cytoskeleton-associated protein ARC is unusual, because newly synthesized Arc mRNA is transported into dendrites, where it accumulates near activated synapses. This process is required for LTP. Farris et al. now report that synaptic activity also triggers Arc degradation. As shown previously, electroconvulsive shock (which activates most synapses) caused Arc mRNA to increase near synapses throughout dendrites of rat dentate granule cells. But subsequent stimulation of the perforant pathway (PP) caused degradation of previously synthesized Arc, while causing newly synthesized Arc mRNA to accumulate selectively near PP synapses. Activity-induced mRNA degradation appeared to be specific for Arc, because another mRNA that accumulates at activated synapses was not depleted after PP stimulation.
Development/Plasticity/Repair
CDYL and EZH2 Suppress BDNF Expression and Dendrite Growth
Cai Qi, Shumeng Liu, Rui Qin, Yu Zhang, Guoqiang Wang, et al.
(see pages 4494–4508)
Cell specification and differentiation are governed by epigenetic modifications that determine whether particular genes are accessible to transcriptional machinery. These modifications, which include methylation and acetylation of histone proteins around which DNA is wrapped, are made by large protein complexes that recognize specific DNA sequences. Chromodomain protein and transcription corepressor (CDYL) interacts with a complex containing the histone-lysine N-methyltransferase EZH2. CDYL stimulates EZH2 activity to suppress gene transcription. Qi et al. report that knocking down CDYL or EZH2 in rodent hippocampal neurons increased the length and branching of dendrites, whereas overexpressing either protein reduced dendritic complexity. Knockdown of either protein did not rescue the effects of overexpressing the other, indicating that the proteins work together to suppress dendritic growth. Of the numerous genes upregulated after CDYL knockdown, the gene encoding brain-derived neurotrophic factor (BDNF) appeared largely responsible for effects on dendritic branching: treating neurons with BDNF rescued the effects of CDYL overexpression and blocking BDNF receptors rescued the effects of knockdown.
Neurolucida drawings of hippocampal neurons from embryonic mice show that knocking down CDYL in vivo (right) increases dendritic length and branching, particularly in basal dendrites. See the article by Qi et al. for details.
Systems/Circuits
Brainstem Cholinergic Neurons Innervate the Striatum
Daniel Dautan, Icnelia Huerta-Ocampo, Ilana B. Witten, Karl Deisseroth, J. Paul Bolam, et al.
(see pages 4509–4518)
The pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) in the brainstem send cholinergic projections throughout the brain. Cholinergic projections from PPN are thought to trigger arousal and vigilance, whereas those from LDT are thought to be involved in motivation to seek reward. Although acetylcholine modulates dopamine release and network activity in the ventral (nucleus accumbens, NAc) and dorsal striatum, LDT and PPN were thought to influence these structures indirectly, via projections to midbrain dopaminergic neurons and to the thalamus; local cholinergic interneurons were thought to be the sole source of acetylcholine within the striatum. Dautan et al. have discovered, however, that rat PPN and LDT also send direct projections to striatum. Rostral PPN neurons densely innervated the dorsolateral striatum, whereas caudal PPN innervated both dorsal and ventral striatum, and LDT neurons projected primarily to the dorsomedial striatum and NAc. Whereas striatal cholinergic interneurons primarily form symmetric synapses on dendritic spines, PPN axons were more likely to form asymmetric synapses on dendritic shafts.
Behavioral/Cognitive
MeCP2 Limits Locomotor Sensitization to Amphetamine
Jie V. Deng, Yehong Wan, Xiaoting Wang, Sonia Cohen, William C. Wetsel, et al.
(see pages 4519–4527)
Like CDYL (discussed above), methyl-DNA binding protein (MeCP2) forms complexes with histone methyltransferases and other proteins that associate with DNA and repress transcription. Through this and possibly other processes, MeCP2 has roles in learning and memory; it may also contribute to plasticity related to drug reward and addiction. Psychostimulants induce phosphorylation of MeCP2 at Ser421 in fast-spiking interneurons (FSIs) in the nucleus accumbens (NAc). To investigate the significance of this modification, Deng et al. created knock-in mice in which wild-type MeCP2 was replaced with a version having a nonphosphorylatable alanine residue at position 421. The Ser421Ala mutation affected neither baseline locomotion nor increases in locomotion after single doses of amphetamine, but long-lasting locomotor sensitization developed after only two daily doses in Ser421Ala mice, 3 days sooner than in wild-type. This rapid sensitization was accompanied by the usual decreases in the excitability of NAc medium spiny neurons and the amphetamine-induced activation of FSIs. These data suggest that phosphorylation of MeCP2 normally limits sensitization to psychostimulants.
