Differing from other subtypes of inhibitory interneuron, chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment (AIS) of targeted pyramidal cells (PCs). However, the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved. Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs, we quantitatively demonstrate that the onset-timing of AIS-GABAergic input, relative to dendritic excitatory glutamatergic inputs, determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC. More specifically, AIS-GABAergic inputs promote the boosting effect of voltage-activated Na⁺ channels on summed synaptic excitation when they precede glutamatergic inputs by >15 ms, while for nearly concurrent excitatory inputs, they primarily produce a shunting inhibition at the AIS. Thus, our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.
Axon Initial Segment ; Axons/physiology* ; Neurons ; Synapses/physiology* ; Pyramidal Cells/physiology* ; Interneurons/physiology* ; Action Potentials/physiology*

The axon initial segment (AIS) is a highly specialized axonal compartment where the action potential is initiated. The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons (PyNs), which likely contributes to their unique spiking properties. However, whether the various characteristics of AISs can be linked to specific PyN subtypes remains unknown. Here, we report that in the prelimbic cortex (PL) of the mouse, two types of PyNs with axon projections either to the contralateral PL or to the ipsilateral basal lateral amygdala, possess distinct AIS properties reflected by morphology, ion channel expression, action potential initiation, and axo-axonic synaptic inputs from chandelier cells. Furthermore, projection-specific AIS diversity is more prominent in the superficial layer than in the deep layer. Thus, our study reveals the cortical layer- and axon projection-specific heterogeneity of PyN AISs, which may endow the spiking of various PyN types with exquisite modulation.
Mice ; Animals ; Axon Initial Segment ; Synapses/physiology* ; Pyramidal Cells/physiology* ; Cerebral Cortex ; Axons/physiology*

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP_E→I). However, the molecular mechanism underlying how γCaMKII mediates LTP_E→I remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Hippocampus/metabolism* ; Interneurons/physiology* ; Long-Term Potentiation/physiology* ; N-Methylaspartate/metabolism* ; Receptors, AMPA/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Synapses/physiology*

Neurons are highly interwoven to form intricate neural circuits that underlie the diverse functions of the brain. Dissecting the anatomical organization of neural circuits is key to deciphering how the brain processes information, produces thoughts, and instructs behaviors. Over the past decades, recombinant viral vectors have become the most commonly used tracing tools to define circuit architecture. In this review, we introduce the current categories of viral tools and their proper application in circuit tracing. We further discuss some advances in viral tracing strategy and prospective innovations of viral tools for future study.
Synapses/physiology* ; Prospective Studies ; Neurons/physiology* ; Genetic Vectors ; Brain/physiology* ; Neural Pathways/physiology*

Synaptic cell adhesion molecules (CAMs) are a type of membrane surface glycoproteins that mediate the structural and functional interactions between pre- and post-synaptic sites. Synaptic CAMs dynamically regulate synaptic activity and plasticity, and their expression and function are modulated by environmental factors. Synaptic CAMs are also important effector molecules of stress response, and mediate the adverse impact of stress on cognition and emotion. In this review, we will summarize the recent progress on the role of synaptic CAMs in stress, and aim to provide insight into the molecular mechanisms and drug development of stress-related disorders.
Cell Adhesion ; Cell Adhesion Molecules ; physiology ; Humans ; Neuronal Plasticity ; Stress, Physiological ; Stress, Psychological ; Synapses

Neuroligins (NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtype-specific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affected GABAergic synapse formation more specifically than NL3, and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.
Animals ; Cell Adhesion Molecules, Neuronal ; physiology ; Cells, Cultured ; Cerebral Cortex ; embryology ; physiology ; GABAergic Neurons ; physiology ; Interneurons ; physiology ; Membrane Proteins ; physiology ; Nerve Tissue Proteins ; physiology ; Protein Isoforms ; physiology ; Pyramidal Cells ; physiology ; Rats, Sprague-Dawley ; Synapses ; physiology

The C1q family is one of the subcomponents of the C1 complex that recognizes immune complexes and initiates the classical pathway of the complement system. In addition, as a pattern recognition receptor (PRR), the C1q family binds to a wide variety of ligands. As a member of the C1q family, the secretory C1q includes several subtypes. The main subtypes are cerebellin (Cbln) and C1q-like protein (C1ql). In the nervous system, secretory C1q is involved in the formation and regulation of various types of synapses, thus secretory C1q is closely related to diseases of the central nervous system. In this article, we review the role of secretory C1q in synapse formation and regulation, and its relationship with some diseases of the central nervous system.
Antigen-Antibody Complex ; Central Nervous System ; Complement C1q ; physiology ; Humans ; Synapses ; physiology

OBJECTIVETo investigate acrylamide (ACR)-induced subacute neurotoxic effects on the central nervous system (CNS) at the synapse level in rats.

METHODSThirty-six Sprague Dawley (SD) rats were randomized into three groups, (1) a 30 mg/kg ACR-treated group, (2) a 50 mg/kg ACR-treated group, and (3) a normal saline (NS)-treated control group. Body weight and neurological changes were recorded each day. At the end of the test, cerebral cortex and cerebellum tissues were harvested and viewed using light and electron microscopy. Additionally, the expression of Synapsin I and P-Synapsin I in the cerebral cortex and cerebellum were investigated.

RESULTSThe 50 mg/kg ACR-treated rats showed a significant reduction in body weight compared with untreated individuals (P < 0.05). Rats exposed to ACR showed a significant increase in gait scores compared with the NS control group (P < 0.05). Histological examination indicated neuronal structural damage in the 50 mg/kg ACR treatment group. The active zone distance (AZD) and the nearest neighbor distance (NND) of synaptic vesicles in the cerebral cortex and cerebellum were increased in both the 30 mg/kg and 50 mg/kg ACR treatment groups. The ratio of the distribution of synaptic vesicles in the readily releasable pool (RRP) was decreased. Furthermore, the expression levels of Synapsin I and P-Synapsin I in the cerebral cortex and cerebellum were decreased in both the 30 mg/kg and 50 mg/kg ACR treatment groups.

CONCLUSIONSubacute ACR exposure contributes to neuropathy in the rat CNS. Functional damage of synaptic proteins and vesicles may be a mechanism of ACR neurotoxicity.

Acrylamide ; toxicity ; Animals ; Cerebellum ; cytology ; drug effects ; Cerebral Cortex ; cytology ; drug effects ; Drug Administration Schedule ; Gait ; Gene Expression Regulation ; drug effects ; Male ; Neurons ; drug effects ; Neurotoxicity Syndromes ; pathology ; Rats ; Rats, Sprague-Dawley ; Synapses ; drug effects ; Synapsins ; genetics ; metabolism ; Synaptic Vesicles ; drug effects ; physiology ; Weight Loss ; drug effects

Our brains are composed of two distinct cell types: neurons and glia. Emerging data from recent investigations show that glial cells, especially astrocytes and microglia, are able to regulate synaptic transmission and thus brain information processing. This suggests that, not only neuronal activity, but communication between neurons and glia also plays a key role in brain function. Thus, it is currently well known that the physiology and pathophysiology of brain function can only be completely understood by considering the interplay between neurons and glia. However, it has not yet been possible to dissect glial cell type-specific roles in higher brain functions in vivo. Meanwhile, the recent development of optogenetics techniques has allowed investigators to manipulate neural activity with unprecedented temporal and spatial precision. Recently, a series of studies suggested the possibility of applying this cutting-edge technique to manipulate glial cell activity. This review briefly discusses the feasibility of optogenetic glia manipulation, which may provide a technical innovation in elucidating the in vivo role of glial cells in complex higher brain functions.
Astrocytes ; Automatic Data Processing ; Brain ; Humans ; Microglia ; Neuroglia* ; Neurons ; Optogenetics* ; Physiology ; Research Personnel ; Synapses ; Synaptic Transmission

Neurotransmission begins with neurotransmitter being released from synaptic vesicles. To achieve this function, synaptic vesicles endure the dynamic "release-recycle" process to maintain the function and structure of presynaptic terminal. Synaptic transmission starts with a single action potential that depolarizes axonal bouton, followed by an increase in the cytosolic calcium concentration that triggers the synaptic vesicle membrane fusion with presynaptic membrane to release neurotransmitter; then the vesicle membrane can be endocytosed for reusing afterwards. This process requires delicate regulation, intermediate steps and dynamic balances. Accumulating evidence showed that the release ability and mobility of synapses varies under different stimulations. Synaptic vesicle heterogeneity has been studied at molecular and cellular levels, hopefully leading to the identification of the relationships between structure and function and understanding how vesicle regulation affects synaptic transmission and plasticity. People are beginning to realize that different types of synapses show diverse presynaptic activities. The steady advances of technology studying synaptic vesicle recycling promote people's understanding of this field. In this review, we discuss the following three aspects of the research progresses on synaptic vesicle recycling: 1) presynaptic vesicle pools and recycling; 2) research progresses on the differences of glutamatergic and GABAergic presynaptic vesicle recycling mechanism and 3) comparison of the technologies used in studying presyanptic vesicle recycling and the latest progress in the technology development in this field.
Action Potentials ; Axons ; physiology ; Calcium ; physiology ; Endocytosis ; Humans ; Presynaptic Terminals ; physiology ; Synapses ; physiology ; Synaptic Transmission ; Synaptic Vesicles ; physiology