J. Neurochem. (2010) 115, 1520–1529. Abstract Soluble amyloid‐β peptide (Aβ) oligomers, known to accumulate in Alzheimer’s disease brains, target excitatory post‐synaptic terminals. This is thought to trigger synapse deterioration, a mechanism possibly underlying memory loss in early stage Alzheimer’s disease. A major unknown is the identity of the receptor(s) targeted by oligomers at synapses. Because oligomers have been shown to interfere with N‐methyl‐d‐aspartate receptor (NMDAR) function and trafficking, we hypothesized that NMDARs might be required for oligomer binding to synapses. An amplicon vector was used to knock‐down NMDARs in mature hippocampal neurons in culture, yielding 90% reduction in dendritic NMDAR expression and blocking neuronal oxidative stress induced by Aβ oligomers, a pathological response that has been shown to be mediated by NMDARs. Remarkably, NMDAR knock‐down abolished oligomer binding to dendrites, indicating that NMDARs are required for synaptic targeting of oligomers. Nevertheless, oligomers do not appear to bind directly to NMDARs as indicated by the fact that both oligomer‐attacked and non‐attacked neurons exhibit similar surface levels of NMDARs. Furthermore, pre‐treatment of neurons with insulin down‐regulates oligomer‐binding sites in the absence of a parallel reduction in surface levels of NMDARs. Establishing that NMDARs are key components of the synaptic oligomer binding complex may illuminate the development of novel approaches to prevent synapse failure triggered by Aβ oligomers.

Mutations in the human gene encoding contactin-associated protein-like 2 (CNTNAP2) have been strongly associated with autism spectrum disorders (ASDs). Cntnap2 ؊/؊ mice recapitulate major features of ASD, including social impairment, reduced vocalizations, and repetitive behavior. In addition, Cntnap2 ؊/؊ mice show reduced cortical neuronal synchrony and develop spontaneous seizures throughout adulthood. As suggested for other forms of ASDs, this phenotype could reflect some form of synaptic dysregulation. However, the impact of lifelong deletion of CNTNAP2 on synaptic function in the brain remains unknown. To address this issue, we have assessed excitatory and inhibitory synaptic transmission in acute hippocampal slices of Cntnap2 ؊/؊ mice. We found that although excitatory transmission was mostly normal, inhibition onto CA1 pyramidal cells was altered in Cntnap2 ؊/؊ mice. Specifically, putative perisomatic, but not dendritic, evoked IPSCs were significantly reduced in these mice. Whereas both inhibitory short-term plasticity and miniature IPSC frequency and amplitude were normal in Cntnap2 ؊/؊ mice, we found an unexpected increase in the frequency of spontaneous, action potential-driven IPSCs. Altered hippocampal inhibition could account for the behavioral phenotype Cntnap2 ؊/؊ mice present later in life. Overall, our findings that Cntnap2 deletion selectively impairs perisomatic hippocampal inhibition while sparing excitation provide additional support for synaptic dysfunction as a common mechanism underlying ASDs.

Soluble oligomers of the amyloid-␤ peptide (A␤Os) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. A␤Os have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of A␤Os. We show that SKF81297, a selective D1/D5 receptor agonist, prevented the reduction in surface levels of AMPA and NMDA receptors induced by A␤Os in hippocampal neurons in culture. Protection by SKF81297 was abrogated by the specific D1/D5 antagonist, SCH23390. Levels of AMPA receptor subunit GluR1 phosphorylated at Ser 845 , which regulates AMPA receptor association with the plasma membrane, were reduced in a calcineurin-dependent manner in the presence of A␤Os, and treatment with SKF81297 prevented this reduction. Establishing the functional relevance of these findings, SKF81297 blocked the impairment of long term potentiation induced by A␤Os in hippocampal slices. Results suggest that D1/D5 receptors may be relevant targets for development of novel pharmacological approaches to prevent synapse failure in AD. Alzheimer disease (AD)2 is the main cause of dementia among the elderly, and current estimates indicate that it affects around 25 million people worldwide (1, 2). Although much is known about the pathophysiology of AD, there is still no cure or effective treatment capable of slowing the progression of the disease. For this reason, development of novel pharmacological strategies for treatment is of critical importance.Considerable evidence indicates that soluble oligomers of the amyloid-␤ peptide (A␤Os) accumulate in the brains of AD patients and are responsible for synapse dysfunction and memory loss in AD (3-5). Among other deleterious actions, A␤Os impair synaptic plasticity, likely leading to memory loss at early stages of the disease. A␤Os have been shown to inhibit long term potentiation (LTP) (4, 6, 7), facilitate the induction of long term depression (LTD) (8, 9), induce internalization of , and increase activation of protein phosphatases, such as calcineurin and protein phosphatase-1 (9, 10, 15, 16), finally leading to spine loss (14).Dopamine receptors have been grouped into two families: D1-type and D2-type (17). The D1 family comprises D1 and D5 receptor subtypes, which are mostly coupled to G␣ s and stimulate production of the second messenger cyclic AMP, leading to activation of protein kinase A (PKA) (17). D1/D5 receptors play important roles in cognition, mediating plasticity and specific aspects of cognitive function, including working and spatial learning and memory processes (18). Stimulation of D...

Alzheimer's disease (AD) is the most prevalent form of dementia in humans. Considerable evidence in AD points to a causal role for altered metabolism of the amyloid precursor protein (APP), with increased levels of peptides derived from APP collectively known as amyloid-b peptides (Ab; Selkoe and Schenk 2003; Haass and Selkoe 2007). The pathological hallmarks of AD are the accumulation of extracellular senile plaques formed by aggregation of Ab, and intracellular tangles formed by the hyperphosphorylated form of the microtubule-associated protein Tau. These pathological alterations are believed to represent endpoints in AD, hence

Dysfunctional cholinergic transmission is thought to underlie, at least in part, memory impairment and cognitive deficits in Alzheimer's disease (AD). However, it is still unclear whether this is a consequence of the loss of cholinergic neurons and elimination of nicotinic acetycholine receptors (nAChRs) in AD brain or of a direct impact of molecular interactions of the amyloid-beta (Abeta) peptide with nAChRs, leading to dysregulation of receptor function. This review examines recent progress in our understanding of the roles of nicotinic receptors in mechanisms of synaptic plasticity, molecular interactions of Abeta with nAChRs, and how Abeta-induced dysregulation of nicotinic receptor function may underlie synaptic failure in AD.