Finally, we analyzed dendritic spines and their postsynaptic densities in CA1. Like for thorny excrescences, 4 weeks of enrichment led to a marked and comparable increase in stratum radiatum spine densities in β-Adducin−/− see more and wild-type mice ( Figure 6A). In further analogy to AZ densities at thorny excrescences,

a detailed analysis of PSD95-positive postsynaptic densities revealed that frequencies of PSD95 puncta per spine decreased markedly upon enriched environment ( Figure 6B), leading to a suppression of CA1 excitatory synapse increases upon enrichment in β-Adducin−/− mice ( Figure 6B). Taken together, these results provide evidence that the presence of β-Adducin is specifically required to establish new synapses under conditions of enhanced plasticity in the adult. In the absence of β-Adducin, environmental enrichment still leads to an increase in dendritic spine numbers, but this increased density of spines is not matched by a corresponding increase in actual synapses, leading to a failure to increase the densities of excitatory synapses at

LMTs and in CA1. Does the failure to establish new synapses upon enrichment in β-Adducin−/− mice affect the beneficial effects of environmental enrichment on learning? To address this question, we focused on learning protocols involving a hippocampal mossy fiber requirement (e.g., Jessberger et al., 2009), where any learning defect may then be rescued by re-expressing GFP-β-Adducin in granule cells. In a first set of experiments, we compared freezing upon contextual fear conditioning in mice housed under control or enriched (4 weeks) conditions. www.selleckchem.com/products/Adriamycin.html As expected, and consistent with stronger learning, re-exposure to context 1 day after learning elicited stronger freezing in enriched wild-type mice ( Figure 7A). When housed under control conditions β-Adducin−/− mice were not noticeably different from wild-type controls in this associative learning task ( Figure 7A; as mentioned in Experimental Procedures, and in good agreement with a previous study [ Rabenstein et al., 2005], the mutant mice did exhibit heptaminol reduced freezing to context when subjected to a milder

conditioning method). However, instead of increasing freezing, enrichment reduced freezing in β-Adducin−/− mice ( Figure 7A). In control experiments the environmental enrichment protocol did enhance fear conditioning-induced freezing in Rab3a−/− mice that lack mossy fiber LTP ( Castillo et al., 1997), indicating that failure by environmental enrichment to increase fear conditioning learning in β-Adducin−/− mice was not just due to a deficit in LTP at this critical synapse ( Figure 7A). Environmental enrichment has been shown to increase neurogenesis in the dentate gyrus in the adult, and adult neurogenesis has been related to improved hippocampal learning ( Deng et al., 2010). Therefore, in a second set of control experiments, we compared adult dentate neurogenesis upon enrichment in wild-type and β-Adducin−/− mice.