Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-_D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.

Alzheimer's disease (AD) is one of the most common neurodegenerative illnesses displaying the highest death rate in the elderly. However, the existing AD diagnostic system remains elusive due to lack of a technology that may ensure enough sensitivity and reproducibility, detection accuracy, and specificity. Herein, a straightforward approach is reported to realize lab‐on‐fiber (LoF) technology for AD biomarker detection based on a D‐shaped single‐mode fiber combined with nanometer‐scale metal‐oxide film. The proposed sensing system, which permits the generation of lossy‐mode resonance (LMR), remarkably increases the evanescent field of light guided through the fiber, and hence the fiber‐surrounding medium interaction. Moreover, such optical sensors are highly repeatable in results and can safely be embedded into a compact and stable microfluidic system. Herein, the specific detection of Tau protein (as one of the classical AD biomarkers that is highly correlated with AD progression) in a complex biofluid with a detection limit of 10⁻¹² m and over a wide concentration range (10⁻³–10 μg mL⁻¹) is successfully demonstrated. The proposed LoF biosensor is an appealing solution for rapid, sub‐microliter dose and highly sensitive detection of analytes at low concentrations, hereby having the potential toward early screening and personalized medicine in AD.

As the population ages, the worldwide prevalence of Alzheimer's disease (AD) as the most common dementia in the elderly is increasing dramatically. However, a long‐term challenge is to achieve rapid and accurate early diagnosis of AD by detecting hallmarks such as amyloid beta (Aβ₄₂). Here, a multi‐channel microfluidic‐based plasmonic fiber‐optic biosensing platform is established for simultaneous detection and differentiation of multiple AD biomarkers. The platform is based on a gold‐coated, highly‐tilted fiber Bragg grating (TFBG) and a custom‐developed microfluidics. TFBG excites a high‐density, narrow‐cladding‐mode spectral comb that overlaps with the broad absorption of surface plasmons for high‐precision interrogation, enabling ultrasensitive monitoring of analytes. In situ detection and in‐parallel discrimination of different forms of Aβ₄₂ in cerebrospinal fluid (CSF) are successfully demonstrated with a detection of limit in the range of ≈30–170 pg mL⁻¹, which is one order of magnitude below the clinical cut‐off level in AD onset, providing high detection sensitivity for early diagnosis of AD. The integration of the TFBG sensor with multi‐channel microfluidics enables simultaneous detection of multiple biomarkers using sub‐µL sample volumes, as well as combining initial binding rate and real‐time response time to differentiate between multiple biomarkers in terms of binding kinetics. With the advantages of multi‐parameter, low consumption, and highly sensitive detection, the sensor represents an urgently needed potentials for large‐scale diagnosis of diseases at early stage.

Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulators, guanine nucleotide exchange factors (GEFs) as the activators and GTPase-activating proteins (GAPs) as the inhibitors. Through coordinated regulation by GEFs and GAPs, Rho GTPases act as converging signaling molecules that convey different upstream signals in the nervous system. So far, more than 70 members of either GEFs or GAPs of Rho GTPases have been identified in mammals, but only a small subset of them have well-known functions. Thus, characterization of important GEFs and GAPs in the nervous system is crucial for the understanding of spatiotemporal dynamics of Rho GTPase activity in different neuronal functions. In this review, we summarize the current understanding of GEFs and GAPs for Rac1, with emphasis on the molecular function and disease implication of these regulators in the nervous system.

We have proposed and experimentally demonstrated a plasmonic titled fiber Bragg grating based biosensor for in-situ detection of the small biomolecule, S-adenosyl-L-homocysteine (AdoHcy). The sensor can also monitor the molecule's interaction with the protein Set7 in real-time. The biosensor is made by coating a 50-nm-thick gold film over an 18 $^\circ$ tilted fiber Bragg grating. A spectrally-dense comb of backward-propagating cladding resonance modes with Q-factor as high as 10 $^4$ is excited due to the tilted grating. The spectral overlap between the excited cladding modes and the broader absorption feature of the surface plasmon makes this device a unique tool for high accuracy measurement of small shifts of plasmon resonance wavelength. Surface biomolecular functionalization of the gold film enables us to not only detect the corresponding biomolecule but also study its interaction with other biomolecules. Our experimental results demonstrate that our biosensor can detect AdoHcy at concentration as low as 1 nM. Furthermore, we have successfully real-time monitored interaction between the protein Set7 and AdoHcy at different concentrations. Our measurements are consistent with the biological theory that the association rate of a pair of biomolecules depends on their concentrations.