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*

To determine the characteristics of spontaneous discharges of hippocampal pyramidal cells (PCs), extracellular neuronal firing in CA1 and CA3 regions of dorsal hippocampus was recorded, the firing modes and interspike interval (ISI) were analyzed with the conventional and nonlinear methods. PCs were discriminated from interneurons using the measurement of action-potential duration and firing rate in this study. There was no significant difference in duration, mean firing frequency, complexity and firing mode between the neurons in CA1 and CA3 regions both in anesthetized and awake animals. The complexity of neurons was higher in awake group than that in anesthetized group, though no difference was found in firing rate. There were differences in the type of pyramidal cells and the coefficient of variance of ISI of neurons. The results obtained from the spontaneous discharges of dorsal hippocampal pyramidal cells reveal some nonlinear and linear aspects in anesthetized and awake states. It seems likely that the combination of conventional and non-linear measurements of the hippocampal pyramidal cells encoding may reflect genuine characteristics of the hippocampal pyramidal cells.
Action Potentials ; physiology ; Animals ; Female ; Guinea Pigs ; Hippocampus ; physiology ; Male ; Microelectrodes ; Neurons ; physiology ; Pyramidal Cells ; physiology

The back-propagating action potential (bpAP) is crucial for neuronal signal integration and synaptic plasticity in dendritic trees. Its properties (velocity and amplitude) can be affected by dendritic morphology. Due to limited spatial resolution, it has been difficult to explore the specific propagation process of bpAPs along dendrites and examine the influence of dendritic morphology, such as the dendrite diameter and branching pattern, using patch-clamp recording. By taking advantage of Optopatch, an all-optical electrophysiological method, we made detailed recordings of the real-time propagation of bpAPs in dendritic trees. We found that the velocity of bpAPs was not uniform in a single dendrite, and the bpAP velocity differed among distinct dendrites of the same neuron. The velocity of a bpAP was positively correlated with the diameter of the dendrite on which it propagated. In addition, when bpAPs passed through a dendritic branch point, their velocity decreased significantly. Similar to velocity, the amplitude of bpAPs was also positively correlated with dendritic diameter, and the attenuation patterns of bpAPs differed among different dendrites. Simulation results from neuron models with different dendritic morphology corresponded well with the experimental results. These findings indicate that the dendritic diameter and branching pattern significantly influence the properties of bpAPs. The diversity among the bpAPs recorded in different neurons was mainly due to differences in dendritic morphology. These results may inspire the construction of neuronal models to predict the propagation of bpAPs in dendrites with enormous variation in morphology, to further illuminate the role of bpAPs in neuronal communication.
Action Potentials/physiology* ; Dendrites/physiology* ; Neurons/physiology* ; Neuronal Plasticity ; Pyramidal Cells/physiology*

The electrical excitability of the dendrites of the cortical neurons was first studied on the apical dendrites of the pyramidal neurons. Professor ZHANG Xiang-Tong (H-T Chang) made important contributions in the fifties of last century on this topic. Through numerous studies later on, it has been established that the electrical excitability of dendrites of different types of neurons, even different dendrites in the same neuron is different. For the apical dendrites of the cortical pyramidal neurons, neither a single nor a train of repetitive action potentials with constant frequency can reach its terminal portion. However, some of the burst repetitive responses with non-constant frequency of the apical dendrite elicited by direct current injected into the soma may reach the terminal portion. This may be due to: (1) the calcium ion concentration in the apical dendrite is increased by the burst activities, which, in turn, increases the electrical excitability of the apical dendrite and /or (2) some retrograde collaterals of axon of the activated soma reach the apical dendrite and release neurotransmitter glutamate, which changes the properties of the voltage-gated ion channels in the apical dendrite. Low electrical excitability of the apical dendrites seems to be essential for the processing of numerous income signals to the terminal portion of the apical dendrites.
Action Potentials ; Animals ; Dendrites ; physiology ; Electrophysiological Phenomena ; Ion Channels ; physiology ; Pyramidal Cells ; physiology ; Synaptic Transmission

Diverse types of GABAergic interneurons tend to specialize in their inhibitory control of various aspects of cortical circuit operations. Among the most distinctive interneuron types, chandelier cells (i.e., axo-axonic cells) are a bona fide cell type that specifically innervates pyramidal cells at the axon initial segment, the site of action potential initiation. Chandelier cells have been speculated to exert ultimate inhibitory control over pyramidal cell spiking. Thus, chandelier cells appear to share multiple similarities with basket cells, not only in firing pattern (fast spiking) and molecular components, but also in potentially perisomatic inhibitory control. Unlike basket cells, however, synaptic recruitment of chandelier cells is little known yet. Here, we examined the mediodorsal thalamocortical input to both chandelier cells and basket cells in medial prefrontal cortex, through combining mouse genetic, optogenetic and electrophysiological approaches. We demonstrated that this thalamocortical input produced initially weak, but facilitated synaptic responses at chandelier cells, which enabled chandelier cells to spike persistently. In contrast, this thalamocortical input evoked initially strong, but rapidly depressed synaptic responses at basket cells, and basket cells only fired at the initiation of input. Overall, the distinct synaptic recruitment dynamics further underscores the differences between chandelier cells and basket cells, suggesting that these two types of fast spiking interneurons play different roles in cortical circuit processing and physiological operation.
Mice ; Animals ; Neurons/physiology* ; Pyramidal Cells/physiology* ; Interneurons ; Action Potentials/physiology* ; Synaptic Transmission

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*

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.
Acoustic Stimulation/methods* ; Neurons/physiology* ; Auditory Cortex/physiology* ; Auditory Perception ; Pyramidal Cells

In order to extract more information from extracellular action potential (EAP) of neurons recorded deep in the brain tissue, we established simulation models of various pyramidal neurons in the hippocampal CA1 region and investigated the effects of dendrite currents, cell morphology and ion mechanisms on the formation of EAP waveforms. The results show that dendrite currents have significant effects on the EAP at the locations far from cell body, but not on those near cell body. The differences of shape of various pyramidal neurons result in large changes in the EAP amplitudes. However, the shapes of these different EAP are very similar. Ion mechanisms, such as calcium channels, have little effect on EAP waveforms. These results provide important information for experimental EAP recordings, EAP data analysis, and developing new methods to extract more neuronal data from EAP.
Action Potentials ; physiology ; Animals ; Computer Simulation ; Hippocampus ; cytology ; physiopathology ; Models, Biological ; Neurons ; physiology ; Pyramidal Cells ; physiopathology ; Rats

To investigate the intracellular mechanism of activity-dependent synapses formation and redistribution, we studied the electrophysiological and morphological characteristics of neurons of the developing visual cortex, and observed the level of synchronism of age and changes in the properties. Whole cell patch-clamp recordings and intracellular biocytin staining were used to record postsynaptic currents (PSCs) from neurons in the visual cortex of Sprague-Dawley rats (postnatal d 4-28). The histological processing was made. There were three types of PSCs in 156 cells: silent response, monosynaptic response and polysynaptic response, during the first developmental month. Before eyes opened the number of the neurons with the silent response (57.3%) was significantly higher than that after the eyes opened (11.9%) (P<0.001). However, the incidence of polysynaptic PSCs increased from 12.4% before eyes opened to 28.9% after eyes opened (P<0.01). During postnatal week 1, all cells were classified as immature. The immature cells had very high input resistances (R(N)>1.0 G Omega), low amplitude (-0.87 mA) and short decay time (-0.98 ms). During postnatal week 4, all cells were mature with lower input resistance (R(N)<310 M Omega), larger amplitude (-66 mA), and longer decay time (-225 ms). From postnatal weeks 1 to 3, the cells had electrophysiological properties that were intermediate between the immature and mature types of cells. With biocytin intracellular staining, five types of neurons were obtained: pyramidal cells, satellite cells, basket cells, neuroglial cells and immature cells. On the basis of their electrophysiological and morphological characteristics, pyramidal cells were classified into three categories: immature, intermediate, and mature cell types. During postnatal week 1, cells were immature with very high input resistance. Morphologically immature cells had short simple dendritic arborizations which incompletely penetrated the layer where the cell body lies. From postnatal weeks 2 to 4, the cells were mature with low input resistance. They were morphologically more complex with dendritic arborizations which completely penetrated the whole layers of the visual cortex. From postnatal weeks 1 to 2, a third, intermediate cell type had electrophysiological properties that were intermediate between the immature and mature cell types. Three distinctive types of pyramidal cells in visual cortex only co-exist during postnatal weeks 1 to 2. Data show that activity-dependent synapes are formed and integrated into local neuronal networks with visual stimulation. In the critical period of visual development, the level of synchronism of age and changes in electrophysiological and morphological properties in the visual cortex is higher than that in the subcortex.
Animals ; Animals, Newborn ; Excitatory Postsynaptic Potentials ; physiology ; Neurons ; cytology ; physiology ; Pyramidal Cells ; cytology ; physiology ; Rats ; Rats, Sprague-Dawley ; Synapses ; metabolism ; physiology ; Visual Cortex ; cytology ; growth & development ; physiology

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