Caution, however, must be employed because much larger sample sizes are required to replicate these findings. How do we reconcile the lack of CNV specificity and the modest CNV burden with the significant increase in de novo CNVs among bipolar cases? Increased CNV size and burden have been shown to be associated with ID in individuals with autism (Girirajan et al., 2011) and there is a general trend that the larger the CNV event, the greater the number of genes affected and the more severe the outcome (Cooper et al., 2011 and Girirajan et al., 2011). The burden of large (>500

kbp) CNVs is highest among cases of ID/MCA (Girirajan et al., 2011) and decreases for autism, schizophrenia, and bipolar disorder (Malhotra et al., 2011 and Sanders et al., 2011) (Figure 1B). Some conditions, such as dyslexia, show no evidence Selleckchem AZD2281 of increased rates or burden of CNVs. It follows that for KRX-0401 in vivo “less severe” adult phenotypes, such as bipolar disorder, de novo CNVs might be smaller in size, affecting fewer genes and/or manifesting

as an excess of duplications. It is well known that certain CNVs are much more variable in their outcome, having been associated with a diverse range of phenotypes, and that the transition to ID among pediatric cases associates with a significant excess of additional CNVs, so-called second “hits” (Girirajan et al., 2011). It is, therefore, conceivable that a subset of bipolar disorder and schizophrenia are part of a spectrum of neurodevelopmental disease where the effects of both de novo and inherited, rare, gene-disruptive and gene-imbalance events are additive. Depending on the underlying genes and their downstream interactions, as the total number of events increases, different thresholds are passed, resulting in outcomes ranging from bipolar disorder to schizophrenia to autism to ID. Comorbidity of these traits within families is the natural extension of this model (Lichtenstein et al., 2009 and Woodberry et al., 2008).

If these trends continue, there is reason to hope that smaller, disruptive CNVs, as well as de novo point mutations, may unveil a larger fraction of the genetic etiology of neuropsychiatric else disease, as has been suggested by preliminary exome sequencing studies of autism and schizophrenia (O’Roak et al., 2011 and Xu et al., 2011). “
“Input processing and storage within dendrites is at the heart of neuronal computation. Yet our understanding of the fundamental operations performed by neurons is incomplete and continues to evolve. Neurons possess numerous mechanisms that allow them to uniquely respond to and store distinct synaptic input patterns, and these capabilities could be used to produce behaviorally related network ensemble activity. Thus the exact level of structure present in normal-experience-induced input patterns remains an important but unresolved issue for which there is both insufficient and conflicting data.