Further evidence that CP-AMPARs are critically involved in synaptic tag and capture at hippocampal CA1 synapses

The synaptic tag and capture (STC) hypothesis provides an important theoretical basis for understanding the synaptic basis of associative learning. We recently provided pharmacological evidence that calcium-permeable AMPA receptors (CP-AMPARs) are a crucial component of this form of heterosynaptic metaplasticity. Here we have investigated two predictions that arise on the basis of CP-AMPARs serving as a trigger of STC. Firstly, we compared the effects of the order in which we delivered a strong theta burst stimulation (TBS) protocol (75 pulses) and a weak TBS protocol (15 pulses) to two independent inputs. We only observed significant heterosynaptic metaplasticity when the strong TBS preceded the weak TBS. Second, we found that pausing stimulation following either the sTBS or the wTBS for ~20 min largely eliminates the heterosynaptic metaplasticity. These observations are consistent with a process that is triggered by the synaptic insertion of CP-AMPARs and provide a framework for establishing the underlying molecular mechanisms.This work was supported by the CIHR (GLC), the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, and Cana‑dian Institute for Health Research operating Grants (CIHR66975 and 84256) (MZ) and the National Honor Scientist Program of the National Research Foundation funded by the South Korea Government (B-KK). This work was also supported by the Brain Canada Foundation through the Canada Brain Research Fund, with the fnancial support of Health Canada

Effects of PI3Kγ overexpression in the hippocampus on synaptic plasticity and spatial learning

Previous studies have shown that a family of phosphoinositide 3-kinases (PI3Ks) plays pivotal roles in the brain; in particular, we previously reported that knockout of the γ isoform of PI3K (PI3Kγ) in mice impaired synaptic plasticity and reduced behavioral flexibility. To further examine the role of PI3Kγ in synaptic plasticity and hippocampus-dependent behavioral tasks we overexpressed p110γ, the catalytic subunit of PI3Kγ, in the hippocampal CA1 region. We found that the overexpression of p110γ impairs NMDA receptor-dependent long-term depression (LTD) and hippocampus-dependent spatial learning in the Morris water maze (MWM) task. In contrast, long-term potentiation (LTP) and contextual fear memory were not affected by p110γ overexpression. These results, together with the previous knockout study, suggest that a critical level of PI3Kγ in the hippocampus is required for successful induction of LTD and normal learning

Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome.

In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS

On the Role of Calcium-Permeable AMPARs in Long-Term Potentiation and Synaptic Tagging in the Rodent Hippocampus

Classically, long-term potentiation (LTP) at hippocampal CA1 synapses is triggered by the synaptic activation of NMDA receptors (NMDARs). More recently, it has been shown that calcium-permeable (CP)-AMPARs can also trigger synaptic plasticity at these synapses. Specifically, their activation is required for the PKA and protein synthesis dependent component of LTP that is typically induced by delivery of spaced trains of high frequency stimulation. Here we present new data that build upon these ideas, including the requirement for low frequency synaptic activation and NMDAR dependence. We also show that a spaced theta burst stimulation (sTBS) protocol induces a heterosynaptic potentiation of baseline responses via activation of CP-AMPARs. Finally, we present data that implicate CP-AMPARs in synaptic tagging and capture, a fundamental process that is associated with the protein synthesis-dependent component of LTP. We have studied how a sTBS can augment the level of LTP generated by a weak TBS (wTBS), delivered 30 min later to an independent input. We show that inhibition of CP-AMPARs during the sTBS eliminates, and that inhibition of CP-AMPARs during the wTBS reduces, this facilitation of LTP. These data suggest that CP-AMPARs are crucial for the protein synthesis-dependent component of LTP and its heterosynaptic nature

Impaired learning and memory in CD38 null mutant mice

CD38 is an enzyme that catalyzes the formation of cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate, both of which are involved in the mobilization of Ca2+ from intracellular stores. Recently, CD38 has been shown to regulate oxytocin release from hypothalamic neurons. Importantly, CD38 mutations are associated with autism spectrum disorders (ASD) and CD38 knockout (CD38(-/-)) mice display ASD-like behavioral phenotypes including deficient parental behavior and poor social recognition memory. Although ASD and learning deficits commonly co-occur, the role of CD38 in learning and memory has not been investigated. We report that CD38(-/-)mice show deficits in various learning and memory tasks such as the Morris water maze, contextual fear conditioning, and the object recognition test. However, either long-term potentiation or long-term depression is not impaired in the hippocampus of CD38(-/-)mice. Our results provide convincing evidence that CD38(-/-)mice show deficits in various learning and memory tasks including spatial and non-spatial memory tasks. Our data demonstrate that CD38 is critical for regulating hippocampus-dependent learning and memory without modulating synaptic plasticity.open1

The Role of Calcium-Permeable AMPARs in Long-Term Potentiation at Principal Neurons in the Rodent Hippocampus

Long-term potentiation (LTP) at hippocampal CA1 synapses is classically triggered by the synaptic activation of NMDA receptors (NMDARs). More recently, it has been shown that calcium-permeable (CP) AMPA receptors (AMPARs) can also trigger synaptic plasticity at these synapses. Here, we review this literature with a focus on recent evidence that CP-AMPARs are critical for the induction of the protein kinase A (PKA)- and protein synthesis-dependent component of LTP