Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.

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Lamellar single crystals grown in dilute solutions can be used as templates for tethered chain analysis. Two series of diblock copolymers, poly(ethylene oxide)-block-polystyrene (PEO-b-PS) and poly(Llactic acid)-block-polystyrene (PLLA-b-PS), were used as model templates to generate tethered PS blocks on the single-crystal basal surfaces. Controlled and tunable reduced tethering density, σ ˜, defined by σπR g 2 (where σ is the tethered chain density and is equal to the reciprocal of the covered area of the chain and R g is the radius of gyration of this tethered chain in its end-free state at the same conditions), could be achieved in a broad range (up to 24) by changing the molecular weights (MW's) of the crystalline and amorphous blocks and by varying the crystallization temperature (T x ) of different PEO-b-PS and PLLA-b-PS solutions. For PEO and PLLA homopolymers crystallized in dilute solutions, the lamellar crystal thicknesses (d CRYST ) were observed to be proportional to the reciprocal undercooling ∆T (where ∆T ) T d -T x and T d is the equilibrium dissolution temperature of the crystals). The σ ˜of the tethered PS chains on the crystal surface increased with decreasing ∆T because at a fixed MW of the PEO or PLLA block, an increase in the d CRYST was evidence of a decrease in the number of folds. When we plotted the relationships between 1/d CRYST and T x for these two series of diblock copolymers, sudden and discontinuous changes of the slopes in some of these were observed at σ ˜) 3.7 (σ ˜*). This was as a result of the drastic interaction change of the neighboring PS tethered chains. An average reduced surface free energy of the tethered PS chains (Γ PS ) was defined and used as a parameter to characterize the PS tethered chain interactions. The relationship between Γ PS and σ ˜showed a discontinuous transition at σ ˜*, which had a close similarity to the hard-sphere-like interaction model. This could be identified as the onset of the tethered PS chain overcrowding in solution. This transition indicates that the extra entropic surface free energy created by the repulsion of tethered PS chains started to affect the nucleation barrier of the PEO or PLLA block crystallization. On the basis of the scaling laws, the onset of highly stretched brush regime could be identified at σ ˜) 14.3 (σ ˜**). In the Γ PS vs σ ˜plot, the transition appears to be continuous. Thus, a crossover regime in the tethered PS chains exists between σ ˜* ) 3.7 and σ ˜** ) 14.3. It is defined as the regime where the interaction of the tethered PS chains undergoes changes from being noninteracting toward penetration to, finally, chain stretching normal to the surface.

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Phosphatidylinositol 3-kinase (PI3K) has been implicated in synaptic plasticity and other neural functions in the brain. However, the role of individual PI3K isoforms in the brain is unclear. We investigated the role of PI3Kγ in hippocampal-dependent synaptic plasticity and cognitive functions. We found that PI3Kγ has a crucial and specific role in NMDA receptor (NMDAR)-mediated synaptic plasticity at mouse Schaffer collateral-commissural synapses. Both genetic deletion and pharmacological inhibition of PI3Kγ disrupted NMDAR long-term depression (LTD) while leaving other forms of synaptic plasticity intact. Accompanying this physiological deficit, the impairment of NMDAR LTD by PI3Kγ blockade was specifically correlated with deficits in behavioral flexibility. These findings suggest that a specific PI3K isoform, PI3Kγ, is critical for NMDAR LTD and some forms of cognitive function. Thus, individual isoforms of PI3Ks may have distinct roles in different types of synaptic plasticity and may therefore influence various kinds of behavior.

Excessive forward movement of lower incisors during presurgical orthodontic treatment could cause alveolar bone loss around the lower incisors; thus, special care should be considered in individuals with mandibular prognathism.

Long-term depression (LTD) is a key form of synaptic plasticity important in learning and information storage in the brain. It has been studied in various cortical regions, including the anterior cingulate cortex (ACC). ACC is a crucial cortical region involved in such emotion-related physiological and pathological conditions as fear memory and chronic pain. In the present study, we used a multielectrode array system to map cingulate LTD in a spatiotemporal manner within the ACC. We found that low-frequency stimulation (1 Hz, 15 min) applied onto deep layer V induced LTD in layers II/III and layers V/VI. Cingulate LTD requires activation of metabotropic glutamate receptors (mGluRs), while L-type voltage-gated calcium channels and NMDA receptors also contribute to its induction. Peripheral amputation of the distal tail impaired ACC LTD, an effect that persisted for at least 2 weeks. The loss of LTD was rescued by priming ACC slices with activation of mGluR1 receptors by coapplying (RS)-3,5-dihydroxyphenylglycine and MPEP, a form of metaplasticity that involved the activation of protein kinase C. Our results provide in vitro evidence of the spatiotemporal properties of ACC LTD in adult mice. We demonstrate that tail amputation causes LTD impairment within the ACC circuit and that this can be rescued by activation of mGluR1.

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