Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation.

The synaptic growth that accompanies 5-HT-induced long-term facilitation of the sensory to motor neuron connection in Aplysia is associated with the internalization of apCAM at the surface membrane of the sensory neuron. We have now used epitope tags to examine the fate of each of the two apCAM isoforms (membrane bound and GPI-linked) and find that only the transmembrane form is internalized. This internalization can be blocked by overexpression of transmembrane constructs with a single point mutation in the two MAPK consensus sites, as well as by injection of a specific MAPK antagonist into sensory neurons. These data suggest MAPK phosphorylation at the membrane is important for the internalization of apCAMs and, thus, may represent an early regulatory step in the growth of new synaptic connections that accompanies long-term facilitation.

Autism spectrum disorder (ASD) refers to a broad spectrum of neurodevelopmental disorders characterized by three central behavioral symptoms: impaired social interaction, impaired social communication, and restricted and repetitive behaviors. However, the symptoms are heterogeneous among patients and a number of ASD mouse models have been generated containing mutations that mimic the mutations found in human patients with ASD. Each mouse model was found to display a unique set of repetitive behaviors. In this review, we summarize the repetitive behaviors of the ASD mouse models and variations found in their neural mechanisms including molecular and electrophysiological features. We also propose potential neuronal mechanisms underlying these repetitive behaviors, focusing on the role of the cortico-basal ganglia-thalamic circuits and brain regions associated with both social and repetitive behaviors. Further understanding of molecular and circuitry mechanisms of the repetitive behaviors associated with ASD is necessary to aid the development of effective treatments for these disorders.

Purpose The clinical importance of intraductal papillary mucinous neoplasm of the pancreas (IPMN) has been increasing with a large number of newly diagnosed IPMN. This study was designed to explore the characteristics of resected IPMN and to determine the predictive factors for malignant and invasive IPMN. Methods Retrospective review of a prospectively collected database was performed on 187 consecutive patients following IPMN surgery between 1994 and 2008 at a tertiary institute. The main duct type IPMN was radiologically defined as main pancreatic duct dilation >5 mm rather than previously defined ≥10 mm. Results The morphologic types of IPMN included 28 main duct (IPMN-M, 15.0%), 118 branch duct (IPMN-Br, 63.1%), and 41 mixed (IPMN-Mixed, 21.9%) IPMNs. There were 23 patients with adenoma, 106 borderline atypia, 15 carcinoma in situ, and 43 invasive carcinoma. Sixty-nine extrapancreatic malignancies were diagnosed in 61 (32.6%) patients. Based on multivariate analysis, IPMN-M was statistically significant predictor of malignancy/ invasiveness (p=0.013/p=0.028). In patients with IPMNBr, the presence of mural nodule was a predictive factor for malignancy/invasiveness (p=0.005/p=0.002). In patients with IPMN-Mixed, mural nodule (p=0.038/p=0.047) and wall thickening (>2 mm, p=0.015/p=0.046) were risk factor for malignancy/invasiveness and elevated CA19-9 (p=0.046) for invasiveness. Conclusions The main pancreatic duct diameter (>5 mm) is a significant predictor for malignancy and invasiveness. Therefore, IPMN patients with main pancreatic duct dilatation (>5 mm) should be considered surgical resection. Mural nodule is the indicator of surgery in IPMN-Br and IPMN-Mixed. In case of IPMN-Mixed with wall thickening or elevated serum CA19-9, surgical resection is recommended.

Cyclic nucleotide-gated channels (CNGCs) transduce external signals required for sensory processes, e.g., photoreception, olfaction, and taste. Nerve growth cone guidance by diffusible attractive and repulsive molecules is regulated by differential growth cone Ca2+ signaling. However, the Ca2+-conducting ion channels that transduce guidance molecule signals are largely unknown. We show that rod-type CNGC-like channels function in the repulsion of cultured Xenopus spinal neuron growth cones by Sema3A, which triggers the production of the cGMP that activates the Xenopus CNGA1 (xCNGA1) subunit-containing channels in interneurons. Downregulation of xCNGA1 or overexpression of a mutant xCNGA1 incapable of binding cGMP abolished CNG currents and converted growth cone repulsion to attraction in response to Sema3A. We also show that Ca2+ entry through xCNGCs is required to mediate the repulsive Sema3A signal. These studies extend our knowledge of the function of CNGCs by demonstrating their requirement for signal transduction in growth cone guidance.