, 2003). Ca2+ activated signal transduction pathways reshape synaptic transmission and neural circuits, in some cases leading to gene activation ( Kauer

and Malenka, 2007). If part of the genetic risk for schizophrenia involves variants in genes involved in formation of α7 nAChRs, then that risk has developmental significance as well. Schizophrenia generally appears in early adulthood, but long before the eruption of hallucinations and delusions, there is neurocognitive www.selleckchem.com/products/ABT-888.html and psychophysiological evidence for abnormalities in children with schizophrenic parents (which increase their risk of the illness). Such is the case with sensory inhibitory deficits. These are apparent at birth in some neonates with a parent who has schizophrenia (Hunter Pifithrin-�� in vivo et al., 2010). Mothers who smoke during pregnancy are also likely to have a neonate with a sensory inhibitory deficit. Chronic exposure to nicotine would be expected to desensitize α7 nAChRs and thus lead to their dysfunction during development. Immature neurons that express α7 nAChRs are more likely to be injured by neonatal nicotine, whereas the expression of heteromeric α4β2∗ nAChRs by more mature neurons may contribute to increased survival (Huang et al., 2007). Like

other nicotinic receptors, α7 nAChRs are thus potential targets for new therapeutic interventions for neural diseases such as schizophrenia. Several clinical trials involving schizophrenics have utilized more specific agonists for α7 nAChRs. 3-(2,4 dimethoxy)-benzylidene-anabaseine, derived from an alkaloid produced by nemertine worms, is a partial agonist at α7 nAChRs. It improves

sensory inhibition in Mannose-binding protein-associated serine protease schizophrenics and also moderately improves their neuropsychological deficits in attention (Olincy et al., 2006). Clinical ratings of their negative symptoms, particularly anhedonia (absence of a sense of pleasure) and alogia (poverty of content in their speech), also improve during treatment. The atypical antipsychotic clozapine uniquely reduces smoking in schizophrenia, possibly because it releases acetylcholine in the hippocampus, activating α7 nAChRs (George et al., 1995). These clinical observations indicate that the patients’ cognitive deficits are more amenable to treatment than many previously believed and their heavy cigarette smoking suggests that prescribed neurobiological treatment does not yet adequately address the brain pathophysiology of schizophrenia. Like many genes expressed in the brain, the expression of α7 nAChRs is maximal during development. α7 nAChRs first appear on neuroblasts as soon as they differentiate from the neuroepithelium, and the peak expression occurs just after birth in rodents (Adams, 2003). In the third trimester, the expression of α7nAChRs in the hippocampus is greater than three times the level in adults.