Like socks that disappear in the dryer, memories cruelly vanish from people with neurodegenerative diseases, such as Alzheimer's disease. Are these memories lost forever, or can the neurodegenerative brain rewire to access them? Fischer et al. report the recovery of memories despite neuron loss in a mouse model of neurodegeneration in a recent article in Nature.
Alzheimer's disease brains accumulate p25, a truncated form of the neuron-specific regulatory subunit for cyclin-dependent kinase 5. p25 binds and constitutively activates Cdk5, and the complex promiscuously phosphorylates cytoskeletal proteins in the diseased brain. Mice overexpressing p25 show age-related neurogeneration and deficits in learning and memory. The authors induced p25 overexpression in forebrain neurons of adult mice.
Environmental enrichment increases neuronal activation and synaptic plasticity. Six weeks after inducing p25 overexpression, the authors enriched home cage environments with running wheels and toys. Mice with p25 overexpression had smaller brains relative to wild-type mice, regardless of their environment. However, four weeks of environmental enrichment improved associative and spatial learning. In p25-overexpressing mice, environmental enrichment increased context-induced fearful freezing in mice taught to associate a context with a shock (contextual fear conditioning) and decreased escape latency, the time necessary to find a hidden platform in the water maze.
Relative to wild-type mice, p25-overexpressing mice showed reduced expression of the neuronal marker NeuN and synaptic proteins, including synaptophysin and PSD-95. Environmental enrichment rescued wild-type expression of synaptic but not neuronal markers in p25-overexpressing mice, suggesting that environmental enrichment increases synapse formation, but does not rescue neuron loss.
Environmental enrichment reestablished lost memories. Four weeks after contextual fear conditioning, the authors induced p25 overexpression in transgenic mice. Six weeks later, these mice froze less than did wild-type mice in response to the shock environment. The authors exposed mice to environmental enrichment or control conditions six weeks after p25 induction. Environmental enrichment rescued wild-type freezing in p25-overexpressing mice, suggesting the recovery of associative memories in mice with neurodegeneration.
How does environmental enrichment recover learning and memory? Epigenetic modification of histones, including histone acetylation and methylation, unwinds chromatin, allowing transcription factors better access to DNA. Environmental enrichment increased acetylation and methylation of histones 3 and 4 in the cortex.
A histone deacetylase inhibitor rescued learning and memory in mice overexpressing p25. When treated daily with the histone deacetylase inhibitor sodium butyrate, these mice showed increased freezing in contextual fear conditioning and decreased escape latency in the water maze relative to vehicle-treated p25-overexpressing mice and were comparable to wild-type mice. Similar to environmental enrichment, sodium butyrate recovered contextual fear conditioning in mice trained before p25 induction, suggesting that prolonged histone acetylation recovers previously formed memories in a mouse model of neurodegeneration.
Sodium butyrate increased synaptophysin expression in p25-overexpressing mice, suggesting that despite neuron loss, histone deacetylase inhibition helps remaining neurons develop circuits to access existing information, according to the authors. Although they will not treat the underlying condition, histone deacetylase inhibitors might recover lost memories and improve cognition in people with advanced stages of Alzheimer's disease.