Spiny Stellate Neurons Research Articles

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal GluN2C N-methyl-D-aspartate receptors.

Genetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate-gated N-methyl-D-aspartate receptors (NMDARs) has been demonstrated for germline defects in the TSC genes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II. We used a rat model of FCD created by in utero electroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C-mediated currents. Neurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory postsynaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time window between postnatal days P9 and P20. Somatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated neuronal NMDARs in neocortices of rat pups. The related and time-restricted local hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR-related brain disorders.

Short-term Dendritic Dynamics of Neonatal Cortical Neurons Revealed by in vivo Imaging with Improved Spatiotemporal Resolution.

Individual neurons in sensory cortices exhibit specific receptive fields based on their dendritic patterns. These dendritic morphologies are established and refined during the neonatal period through activity-dependent plasticity. This process can be visualized using two-photon in vivo time-lapse imaging, but sufficient spatiotemporal resolution is essential. We previously examined dendritic patterning from spiny stellate (SS) neurons, the major type of layer 4 (L4) neurons, in the mouse primary somatosensory cortex (barrel cortex), where mature dendrites display a strong orientation bias toward the barrel center. Longitudinal imaging at 8-h intervals revealed the long-term dynamics by which SS neurons acquire this unique dendritic pattern. However, the spatiotemporal resolution was insufficient to detect the more rapid changes in SS neuron dendrite morphology during the critical neonatal period. In the current study, we imaged neonatal L4 neurons hourly for 8 h and improved the spatial resolution by uniform cell-surface labeling. The improved spatiotemporal resolution allowed detection of precise changes in dendrite morphology and revealed aspects of short-term dendritic dynamics unique to the neonatal period. Basal dendrites of barrel cortex L4 neurons were highly dynamic. In particular, both barrel-inner and barrel-outer dendrites (trees and branches) emerged/elongated and disappeared/retracted at similarly high frequencies, suggesting that SS neurons acquire biased dendrite patterns through rapid trial-and-error emergence, elongation, elimination, and retraction of dendritic trees and branches. We also found correlations between morphology and behavior (elongation/retraction) of dendritic tips. Thus, the current study revealed short-term dynamics and related features of cortical neuron dendrites during refinement.Significance StatementThe formation of proper dendritic patterns during early postnatal development is essential for normal neuronal circuit function in adulthood. To elucidate the mechanisms responsible for this refinement, in vivo imaging with high spatiotemporal resolution is useful. Our previous long-term in vivo imaging studies have clarified aspects of dendritic refinement mechanism; however, due to the long intervals (8-h) between image acquisitions, rapid changes in dendritic morphology were missed. Here hourly in vivo time-lapse imaging of neonatal mouse barrel cortex over 8 h revealed the rapid changes in the dendrite morphology of layer 4 neurons, thereby providing a more comprehensive record of dendritic refinement during postnatal development for mechanistic analysis.

Thalamocortical control of cell-type specificity drives circuits for processing whisker-related information in mouse barrel cortex

Excitatory spiny stellate neurons are prominently featured in the cortical circuits of sensory modalities that provide high salience and high acuity representations of the environment. These specialized neurons are considered developmentally linked to bottom-up inputs from the thalamus, however, the molecular mechanisms underlying their diversification and function are unknown. Here, we investigated this in mouse somatosensory cortex, where spiny stellate neurons and pyramidal neurons have distinct roles in processing whisker-evoked signals. Utilizing spatial transcriptomics, we identified reciprocal patterns of gene expression which correlated with these cell-types and were linked to innervation by specific thalamic inputs during development. Genetic manipulation that prevents the acquisition of spiny stellate fate highlighted an important role for these neurons in processing distinct whisker signals within functional cortical columns, and as a key driver in the formation of specific whisker-related circuits in the cortex.

Golgi polarity shift instructs dendritic refinement in the neonatal cortex by mediating NMDA receptor signaling

Dendritic refinement is a critical component of activity-dependent neuronal circuit maturation, through which individual neurons establish specific connectivity with their target axons. Here, we demonstrate that the developmental shift of Golgi polarity is a key process in dendritic refinement. During neonatal development, the Golgi apparatus in layer 4 spiny stellate (SS) neurons in the mouse barrel cortex lose their original apical positioning and acquire laterally polarized distributions. This lateral Golgi polarity, which is oriented toward the barrel center, peaks on postnatal days 5-7 (P5-P7) and disappears by P15, which aligns with the developmental time course of SS neuron dendritic refinement. Genetic ablation of N-methyl-D-aspartate (NMDA) receptors, key players in dendritic refinement, disturbs the lateral Golgi polarity. Golgi polarity manipulation disrupts the asymmetric dendritic projection pattern and the primary-whisker-specific response of SS neurons. Our results elucidate activity-dependent Golgi dynamics and their critical role in developmental neuronal circuit refinement.

Single-neuron analysis of dendrites and axons reveals the network organization in mouse prefrontal cortex.

The structures of dendrites and axons form the basis for the connectivity of neural network, but their precise relationship at single-neuron level remains unclear. Here we report the complete dendrite and axon morphology of nearly 2,000 neurons in mouse prefrontal cortex (PFC). We identified morphological variations of somata, dendrites and axons across laminar layers and PFC subregions and the general rules of somatodendritic scaling with cytoarchitecture. We uncovered 24 morphologically distinguishable dendrite subtypes in 1,515 pyramidal projection neurons and 405 atypical pyramidal projection neurons and spiny stellate neurons with unique axon projection patterns. Furthermore, correspondence analysis among dendrites, local axons and long-range axons revealed coherent morphological changes associated with electrophysiological phenotypes. Finally, integrative dendrite-axon analysis uncovered the organization of potential intra-column, inter-hemispheric and inter-column connectivity among projection neuron types in PFC. Together, our study provides a comprehensive structural repertoire for the reconstruction and analysis of PFC neural network.

Normal connectivity of thalamorecipient networks in barrel equivalents of the reeler cortex.

The reeler mouse mutant has long served as a primary model to study the development of cortical layers, which is governed by the extracellular glycoprotein reelin secreted by Cajal-Retzius cells. Because layers organize local and long-range circuits for sensory processing, we investigated whether intracortical connectivity is compromised by reelin deficiency in this model. We generated a transgenic reeler mutant (we used both sexes), in which layer 4-fated spiny stellate neurons are labeled with tdTomato and applied slice electrophysiology and immunohistochemistry with synaptotagmin-2 to study the circuitry between the major thalamorecipient cell types, namely excitatory spiny stellate and inhibitory fast-spiking (putative basket) cells. In the reeler mouse, spiny stellate cells are clustered into barrel equivalents. In these clusters, we found that intrinsic physiology, connectivity, and morphology of spiny stellate and fast-spiking, putative basket cells does not significantly differ between reeler and controls. Properties of unitary connections, including connection probability, were very comparable in excitatory cell pairs and spiny stellate/fast-spiking cell pairs, suggesting an intact excitation-inhibition balance at the first stage of cortical sensory information processing. Together with previous findings, this suggests that thalamorecipient circuitry in the barrel cortex develops and functions independently of proper cortical lamination and postnatal reelin signaling.

Ras GTPase-activating proteins control neuronal circuit development in barrel cortex layer 4.

The cerebral cortex comprises a complex and exquisite network of neuronal circuits that is formed during development. To explore the molecular mechanisms involved in cortical circuit formation, the tactile somatosensory pathway that connects the whiskers and cortex of rodents is a useful model. Here, we analyzed the roles of Ras GTPase-activating proteins (RasGAPs) in the circuit formation in the somatosensory cortex layer 4 (L4). We suppressed the function of RasGAPs in L4 neurons using Supernova RNAi, a plasmid vector-based sparse cell gene knockdown (KD) system. The results showed disrupted dendritic pattern formation of L4 spiny stellate neurons on the barrel edge by RasGAP KD. Furthermore, the number of presynaptic boutons on L4 neurons was reduced by RasGAP KD. These results demonstrate the essential roles of RasGAPs in circuit formation in the cerebral cortex and imply that developmental changes in dendrites and synapses in RasGAP KD neurons may be related to cognitive disabilities in RasGAP-deficient individuals, such as patients with neurofibromatosis type 1.

Removal of a compressive mass causes a transient disruption of blood-brain barrier but a long-term recovery of spiny stellate neurons in the rat somatosensory cortex.

In the cranial cavity, a space-occupying mass such as epidural hematoma usually leads to compression of brain. Removal of a large compressive mass under the cranial vault is critical to the patients. The purpose of this study was to examine whether and to what extent epidural decompression of the rat primary somatosensory cortex affects the underlying microvessels, spiny stellate neurons and their afferent fibers. Rats received epidural decompression with preceding 1-week compression by implantation of a bead. The thickness of cortex was measured using brain coronal sections. The permeability of blood-brain barrier (BBB) was assessed by Evans Blue and immunoglobulin G extravasation. The dendrites and dendritic spines of the spiny stellate neurons were revealed by Golgi-Cox staining and analyzed. In addition, the thalamocortical afferent (TCA) fibers in the cortex were illustrated using anterograde tracing and examined. The cortex gradually regained its thickness over time and became comparable to the sham group at 3 days after decompression. Although the diameter of cortical microvessels were unaltered, a transient disruption of the BBB was observed at 6 hours and 1 day after decompression. Nevertheless, no brain edema was detected. In contrast, the dendrites and dendritic spines of the spiny stellate neurons and the TCA fibers were markedly restored from 2 weeks to 3 months after decompression. Epidural decompression caused a breakdown of the BBB, which was early-occurring and short-lasting. In contrast, epidural decompression facilitated a late-onset and prolonged recovery of the spiny stellate neurons and their afferent fibers.

Comparative neuroanatomical study of the amygdala and fear conditioning in Nigerian breeds of Artiodactyla: Sheep (Uda) and goats (Red Sokoto)

The aim of this study was to evaluate fear condition responses in sheep and goat and to relate this to the neuroarchitecture of their amygdala. Forty adult sheep (Uda breed) and 40 adult goats (Red Sokoto breed) were fear-conditioned by associating the sound of a car horn (neutral stimuli) with water spray (aversive stimuli) and the fear response was determined by direct observation of the behavior of the sheep and goats and measuring their flight distances and escape time. Eight groups were studied, each comprising of 10 animals (five sheep and five goats). Goats and sheep were tested alternately in the morning of every day of the week for three consecutive weeks, in which 4 days was used for habituation and 3 days for testing. Histologically, neurons in the central and basolateral complex of the amygdala were studied and analyzed using Nissl and golgi staines. Behaviorally, goats elicited an active avoidance response expressed as flight with concomitant intense flight distances (p < .001) compared to sheep. Although, sheep had larger brain parameters, it showed attenuated basolateral amygdala cytoarchitecture consistent with reduced fear perception and response. Goats had significantly more densely distributed pyramidal and spiny stellate neurons in the basolateral amygdala while sheep showed more non-pyramidal and aspiny neurons. These results provide interesting practical perspectives on how adaptions in the amygdala coincides with alterations in fear conditioning in domestic animals and may be the basis for the higher incidence of the sheep in automobile accidents than goats in developing countries especially Africa.

In vivo imaging of neural circuit formation in the neonatal mouse barrel cortex

Higher brain function in mammals primarily relies on complex yet sophisticated neuronal circuits in the neocortex. In early developmental stages, neocortical circuits are coarse. Mostly postnatally, the circuits are reorganized to establish mature precise connectivity, in an activity-dependent manner. These connections underlie adult brain function. The rodent somatosensory cortex (barrel cortex) contains a barrel map in layer 4 (L4) and has been considered an ideal model for the study of postnatal neuronal circuit formation since the first report of barrels in 1970. Recently, two-photon microscopy has been used for analyses of neuronal circuit formation in the mammalian brain during early postnatal development. These studies have further highlighted the mouse barrel cortex as an ideal model. In particular, the unique dendritic projection pattern of barrel cortex L4 spiny stellate neurons (barrel neurons) is key for the precise one-to-one functional relationship between whiskers and barrels and thus an important target of studies. In this article, I will review the morphological aspects of postnatal development of neocortical circuits revealed by recent two-photon in vivo imaging studies of the mouse barrel cortex and other related works. The focus of this review will be on barrel neuron dendritic refinement during neonatal development.

A Translaminar Genetic Logic for the Circuit Identity of Intracortically Projecting Neurons

Neurons of the neocortex are organized into six radial layers, which have appeared at different times during evolution, with the superficial layers representing a more recent acquisition. Input to the neocortex predominantly reaches superficial layers (SL, i.e., layers (L) 2-4), while output is generated in deep layers (DL, i.e., L5-6) [1]. Intracortical connections, which bridge input and output pathways, are key components of cortical circuits because they allow the propagation and processing of information within the neocortex. Two main types of intracortically projecting neurons (ICPN) can be distinguished by their axonal features: L4 spiny stellate neurons (SSN) with short axons projecting locally within cortical columns [2-5], and SL and DL long-range projection neurons, including callosally projecting neurons (CPNSL and CPNDL) [5, 6]. Here, we investigate the molecular hallmarks that distinguish SSN, CPNSL, and CPNDL and relate their transcriptional signatures with their output connectivity. Specifically, taking advantage of the presence of CPN in both SL and DL, we identify lamina-independent genetic hallmarks of a constant projection motif (i.e., interhemispheric projection). By performing unbiased transcriptomic comparisons between CPNSL, CPNDL and SSN, we provide specific molecular profiles for each of these populations and show that target identity supersedes laminar position in defining ICPN transcriptional diversity. Together, these findings reveal a projection-based organization of transcriptional programs across cortical layers, which we propose reflects conserved strategy to protect canonical circuit structure (and hence function) across a diverse range of neuroanatomies.

Differential dynamics of cortical neuron dendritic trees revealed by long-term in vivo imaging in neonates

Proper neuronal circuit function relies on precise dendritic projection, which is established through activity-dependent refinement during early postnatal development. Here we revealed dynamics of dendritic refinement in the mammalian brain by conducting long-term imaging of the neonatal mouse barrel cortex. By “retrospective” analyses, we identified “prospective” barrel-edge spiny stellate (SS) neurons in early neonates, which had an apical dendrite and primitive basal dendrites (BDs). These neurons retracted the apical dendrite gradually and established strong BD orientation bias through continuous “dendritic tree” turnover. A greater chance of survival was given to BD trees emerged in the barrel-center side, where thalamocortical axons (TCAs) cluster. When the spatial bias of TCA inputs to SS neurons was lost, BD tree turnover was suppressed, and most BD trees became stable and elaborated mildly. Thus, barrel-edge SS neurons could establish the characteristic BD projection pattern through differential dynamics of dendritic trees induced by spatially biased inputs.

Structural and functional differences in the barrel cortex of Mecp2 null mice.

Functional deficits in sensory systems are commonly noted in neurodevelopmental disorders, such as the Rett syndrome (RTT). Defects in methyl CpG binding protein gene (MECP2) largely accounts for RTT. Manipulations of the Mecp2 gene in mice provide useful models to probe into various aspects of brain development associated with the RTT. In this study, we focused on the somatosensory cortical phenotype in the Bird mouse model of RTT. We used voltage-sensitive dye imaging to evaluate whisker sensory evoked activity in the barrel cortex of mice. We coupled this functional assay with morphological analyses in postnatal mice and investigated the dendritic differentiation of barrel neurons and individual thalamocortical axon (TCA) arbors that synapse with them. We show that in Mecp2-deficient male mice, whisker-evoked activity is roughly topographic but weak in the barrel cortex. At the morphological level, we find that TCA arbors fail to develop into discrete, concentrated patches in barrel hollows, and the complexity of the dendritic branches in layer IV spiny stellate neurons is reduced. Collectively, our results indicate significant structural and functional impairments in the barrel cortex of the Bird mouse line, a popular animal model for the RTT. Such structural and functional anomalies in the primary somatosensory cortex may underlie orofacial tactile sensitivity issues and sensorimotor stereotypies characteristic of RTT.

MGluR5 Tunes NGF/TrkA Signaling to Orient Spiny Stellate Neuron Dendrites Toward Thalamocortical Axons During Whisker-Barrel Map Formation.

Neurons receive and integrate synaptic inputs at their dendrites, thus dendritic patterning shapes neural connectivity and behavior. Aberrant dendritogenesis is present in neurodevelopmental disorders such as Down's syndrome and autism. Abnormal glutamatergic signaling has been observed in these diseases, as has dysfunction of the metabotropic glutamate receptor 5 (mGluR5). Deleting mGluR5 in cortical glutamatergic neurons disrupted their coordinated dendritic outgrowth toward thalamocortical axons and perturbed somatosensory circuits. Here we show that mGluR5 loss-of-function disrupts dendritogenesis of cortical neurons by increasing mRNA levels of nerve growth factor (NGF) and fibroblast growth factor 10 (FGF10), in part through calcium-permeable AMPA receptors (CP-AMPARs), as the whisker-barrel map is forming. Postnatal NGF and FGF10 expression in cortical layer IV spiny stellate neurons differentially impacted dendritic patterns. Remarkably, NGF-expressing neurons exhibited dendritic patterns resembling mGluR5 knockout neurons: increased total dendritic length/complexity and reduced polarity. Furthermore, suppressing the kinase activity of TrkA, a major NGF receptor, prevents aberrant dendritic patterning in barrel cortex of mGluR5 knockout neurons. These results reveal novel roles for NGF-TrkA signaling and CP-AMPARs for proper dendritic development of cortical neurons. This is the first in vivo demonstration that cortical neuronal NGF expression modulates dendritic patterning during postnatal brain development.

High- and low-conductance NMDA receptors are present in layer 4 spiny stellate and layer 2/3 pyramidal neurons of mouse barrel cortex.

N‐Methyl‐D‐aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate in the mammalian brain and are important in synaptic function and plasticity, but are also found in extrasynaptic locations and influence neuronal excitability. There are different NMDA receptor subtypes which differ in their single‐channel conductance. Recently, synaptic plasticity has been studied in the mouse barrel cortex, the primary sensory cortex for input from the animal's whiskers. Pharmacological data imply the presence of low‐conductance NMDA receptors in spiny stellate neurons of cortical layer 4, but of high‐conductance NMDA receptors in pyramidal neurons of layer 2/3. Here, to obtain complementary electrophysiological information on the functional NMDA receptors expressed in layer 4 and layer 2/3 neurons, single NMDA receptor currents were recorded with the patch‐clamp method. Both cell types were found to contain high‐conductance as well as low‐conductance NMDA receptors. The results are consistent with the reported pharmacological data on synaptic plasticity, and with previous claims of a prominent role of low‐conductance NMDA receptors in layer 4 spiny stellate neurons, including broad integration, amplification and distribution of excitation within the barrel in response to whisker stimulation, as well as modulation of excitability by ambient glutamate. However, layer 4 cells also expressed high‐conductance NMDA receptors. The presence of low‐conductance NMDA receptors in layer 2/3 pyramidal neurons suggests that some of these functions may be shared with layer 4 spiny stellate neurons.

Intracortical Network Effects Preserve Thalamocortical Input Efficacy in a Cortex Without Layers.

Layer IV (LIV) of the rodent somatosensory cortex contains the somatotopic barrel field. Barrels receive much of the sensory input to the cortex through innervation by thalamocortical axons from the ventral posteromedial nucleus. In the reeler mouse, the absence of cortical layers results in the formation of mispositioned barrel-equivalent clusters of LIV fated neurons. Although functional imaging suggests that sensory input activates the cortex, little is known about the cellular and synaptic properties of identified excitatory neurons of the reeler cortex. We examined the properties of thalamic input to spiny stellate (SpS) neurons in the reeler cortex with in vitro electrophysiology, optogenetics, and subcellular channelrhodopsin-2-assisted circuit mapping (sCRACM). Our results indicate that reeler SpS neurons receive direct but weakened input from the thalamus, with a dispersed spatial distribution along the somatodendritic arbor. These results further document subtle alterations in functional connectivity concomitant of absent layering in the reeler mutant. We suggest that intracortical amplification mechanisms compensate for this weakening in order to allow reliable sensory transmission to the mutant neocortex.

MGluR5 Exerts Cell-Autonomous Influences on the Functional and Anatomical Development of Layer IV Cortical Neurons in the Mouse Primary Somatosensory Cortex.

Glutamate neurotransmission refines synaptic connections to establish the precise neural circuits underlying sensory processing. Deleting metabotropic glutamate receptor 5 (mGluR5) in mice perturbs cortical somatosensory map formation in the primary somatosensory (S1) cortex at both functional and anatomical levels. To examine the cell-autonomous influences of mGluR5 signaling in the morphological and functional development of layer IV spiny stellate glutamatergic neurons receiving sensory input, mGluR5 genetic mosaic mice were generated through in utero electroporation. In the S1 cortex of these mosaic brains, we found that most wild-type neurons were located in barrel rings encircling thalamocortical axon (TCA) clusters while mGluR5 knock-out (KO) neurons were placed in the septal area, the cell-sparse region separating barrels. These KO neurons often displayed a symmetrical dendritic morphology with increased dendritic complexity, in contrast to the polarized pattern of wild-type neurons. The dendritic spine density of mGluR5 KO spiny stellate neurons was significantly higher than in wild-type neurons. Whole-cell electrophysiological recordings detected a significant increase in the frequencies of spontaneous and miniature excitatory postsynaptic events in mGluR5 KO neurons compared with neighboring wild-type neurons. Our mosaic analysis provides strong evidence supporting the cell-autonomous influence of mGluR5 signaling on the functional and anatomical development of cortical glutamatergic neurons. Specifically, mGluR5 is required in cortical glutamatergic neurons for the following processes: (1) the placement of cortical glutamatergic neurons close to TCA clusters; (2) the regulation of dendritic complexity and outgrowth toward TCA clusters; (3) spinogenesis; and (4) tuning of excitatory inputs. Glutamatergic transmission plays a critical role in cortical circuit formation. Its dysfunction has been proposed as a core factor in the etiology of many neurological diseases. Here we conducted mosaic analysis to reveal the cell-autonomous role of the metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5 is required for several key steps in wiring up the thalamocortical connections to form the cortical somatosensory map. mGluR5-dependent processes during early postnatal brain development affect the following: (1) placement of activity-directed cortical neurons; (2) regulation of polarized dendritic outgrowth toward thalamocortical axons relaying sensory information, (3) synaptogenesis; and (4) development of functional connectivity in spiny stellate neurons. Perturbing mGluR5 expression could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.

Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission.

Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood.

Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex.

Brain derived neurotrophic factor (BDNF) plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However, it is unclear how specific BDNF’s effects are on different circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV), we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF’s effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e., feed-forward inhibition); whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF.

Reduced chemical and electrical connections of fast-spiking interneurons in experimental cortical dysplasia.

Aberrant neural connections are regarded as a principal factor contributing to epileptogenesis. This study examined chemical and electrical connections between fast-spiking (FS), parvalbumin (PV)-immunoreactive (FS-PV) interneurons and regular-spiking (RS) neurons (pyramidal neurons or spiny stellate neurons) in a rat model of prenatal irradiation-induced cortical dysplasia. Presynaptic action potentials were evoked by current injection and the elicited unitary inhibitory or excitatory postsynaptic potentials (uIPSPs or uEPSPs) were recorded in the postsynaptic cell. In dysplastic cortex, connection rates between presynaptic FS-PV interneurons and postsynaptic RS neurons and FS-PV interneurons, and uIPSP amplitudes were significantly smaller than controls, but both failure rates and coefficient of variation of uIPSP amplitudes were larger than controls. In contrast, connection rates from RS neurons to FS-PV interneurons and uEPSPs amplitude were similar in the two groups. Assessment of the paired pulse ratio showed a significant decrease in synaptic release probability at FS-PV interneuronal terminals, and the density of terminal boutons on axons of biocytin-filled FS-PV interneurons was also decreased, suggesting presynaptic dysfunction in chemical synapses formed by FS-PV interneurons. Electrical connections were observed between FS-PV interneurons, and the connection rates and coupling coefficients were smaller in dysplastic cortex than controls. In dysplastic cortex, we found a reduced synaptic efficiency for uIPSPs originating from FS-PV interneurons regardless of the type of target cell, and impaired electrical connections between FS-PV interneurons. This expands our understanding of the fundamental impairment of inhibition in this model and may have relevance for certain types of human cortical dysplasia.