Learning and memory

Methylphenidate facilitates learning-induced amygdala plasticity Tye, K. M. et al. Nature Neurosci. 13, 475–481 (2010)

Methylphenidate (Ritalin) is used to treat attention deficit–hyperactivity disorder, but its mechanism of action is unclear. The authors studied how methylphenidate affected the performance of rats in a cue–reward learning paradigm. Methylphenidate enhanced learning by modulating excitatory synaptic plasticity in cortico-amygdala synapses through increased activation of dopamine receptors in the lateral amygdala. Furthermore, different dopamine receptor subtypes enhanced different aspects of the learning task. These findings suggest a crucial role for dopamine in lateral amygdala-dependent learning.

Epigenetics

Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons Feng, J. et al. Nature Neurosci. 13, 423–430 (2010)

DNA methyltransferase 1 (DNMT1) and DNMT3A regulate methylation patterns in rapidly dividing cells. Their expression in adult postmitotic neurons suggested that they might have additional functions in the adult nervous system. Here, the authors generated conditional-knockout mice expressing DNMT1 and DNMT3A exclusively in postnatal forebrain neurons. The Dnmt1–Dnmt3a double knockout, but not the single knockouts, showed deficits in hippocampal synaptic plasticity and learning and memory, as well as altered gene expression. Thus, DNMT1 and DNMT3A have overlapping functions and are required for the maintenance of DNA methylation in postmitotic neurons.

Neurodegenerative disease

Caspase activation precedes and leads to tangles de Calignon, A. et al. Nature 31 March 2010 (doi:10.1038/nature08890)

The order of events leading to neurodegeneration in Alzheimer's disease and frontotemporal dementia is debated. Here, the authors use in vivo multiphoton imaging to show that, in transgenic mice carrying a mutated human tau gene, caspase activation occurs before the formation of fibrillar tau deposits (tangles). Moreover, expressing a construct that mimics caspase-cleaved tau in wild-type mice induced the formation of tau aggregates that included full-length tau. The authors postulate that caspase-cleaved tau initiates tangle formation and then normal tau is recruited to the aggregates.

Development

A critical role for α4βδ GABAA receptors in shaping learning deficits at puberty in mice Shen, H. et al. Science 327, 1515–1518 (2010)

The onset of puberty marks a decline in learning ability. Investigating the underlying mechanisms, the authors showed that α4βδ-containing GABAARs are expressed perisynaptically at excitatory hippocampal CA1 synapses at a higher level in pubertal than in prepubertal mice. Pubertal mice show no NMDAR-dependent hippocampal long-term potentiation and impaired hippocampus-dependent learning. These deficits were absent in pubertal mice lacking the δ subunit and could be reversed by allopregnanolone, a GABAAR modulator, suggesting a potential use for this steroid as a 'smart drug' for adolescents.