Mouse Sensorimotor Cortex Research Articles

From Individual to Population: Circuit Organization of Pyramidal Tract and Intratelencephalic Neurons in Mouse Sensorimotor Cortex.

The sensorimotor cortex participates in diverse functions with different reciprocally connected subregions and projection-defined pyramidal neuron types therein, while the fundamental organizational logic of its circuit elements at the single-cell level is still largely unclear. Here, using mouse Cre driver lines and high-resolution whole-brain imaging to selectively trace the axons and dendrites of cortical pyramidal tract (PT) and intratelencephalic (IT) neurons, we reconstructed the complete morphology of 1,023 pyramidal neurons and generated a projectome of 6 subregions within the sensorimotor cortex. Our morphological data revealed substantial hierarchical and layer differences in the axonal innervation patterns of pyramidal neurons. We found that neurons located in the medial motor cortex had more diverse projection patterns than those in the lateral motor and sensory cortices. The morphological characteristics of IT neurons in layer 5 were more complex than those in layer 2/3. Furthermore, the soma location and morphological characteristics of individual neurons exhibited topographic correspondence. Different subregions and layers were composed of different proportions of projection subtypes that innervate downstream areas differentially. While the axonal terminals of PT neuronal population in each cortical subregion were distributed in specific subdomains of the superior colliculus (SC) and zona incerta (ZI), single neurons selectively innervated a combination of these projection targets. Overall, our data provide a comprehensive list of projection types of pyramidal neurons in the sensorimotor cortex and begin to unveil the organizational principle of these projection types in different subregions and layers.

Learning-related congruent and incongruent changes of excitation and inhibition in distinct cortical areas.

Excitatory and inhibitory neurons in diverse cortical regions are likely to contribute differentially to the transformation of sensory information into goal-directed motor plans. Here, we investigate the relative changes across mouse sensorimotor cortex in the activity of putative excitatory and inhibitory neurons-categorized as regular spiking (RS) or fast spiking (FS) according to their action potential (AP) waveform-comparing before and after learning of a whisker detection task with delayed licking as perceptual report. Surprisingly, we found that the whisker-evoked activity of RS versus FS neurons changed in opposite directions after learning in primary and secondary whisker motor cortices, while it changed similarly in primary and secondary orofacial motor cortices. Our results suggest that changes in the balance of excitation and inhibition in local circuits concurrent with changes in the long-range synaptic inputs in distinct cortical regions might contribute to performance of delayed sensory-to-motor transformation.

Flexible simultaneous mesoscale two-photon imaging of neural activity at high speeds

Understanding brain function requires monitoring local and global brain dynamics. Two-photon imaging of the brain across mesoscopic scales has presented trade-offs between imaging area and acquisition speed. We describe a flexible cellular resolution two-photon microscope capable of simultaneous video rate acquisition of four independently targetable brain regions spanning an approximate five-millimeter field of view. With this system, we demonstrate the ability to measure calcium activity across mouse sensorimotor cortex at behaviorally relevant timescales.

Cortical transcriptome analysis after spinal cord injury reveals the regenerative mechanism of central nervous system in CRMP2 knock-in mice.

Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2 (CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function after spinal cord injury (SCI). We aimed to reveal the intracellular mechanism in axotomized neurons in the CRMP2 knock-in (CRMP2KI) mouse model by performing transcriptome analysis in mouse sensorimotor cortex using micro-dissection punching system. Prior to that, we analyzed the structural pathophysiology in axotomized or neighboring neurons after SCI and found that somatic atrophy and dendritic spine reduction in sensorimotor cortex were suppressed in CRMP2KI mice. Further analysis of the transcriptome has aided in the identification of four hemoglobin genes Hba-a1, Hba-a2, Hbb-bs, and Hbb-bt that are significantly upregulated in wild-type mice with concomitant upregulation of genes involved in the oxidative phosphorylation and ribosomal pathways after SCI. However, we observed substantial upregulation in channel activity genes and downregulation of genes regulating vesicles, synaptic function, glial cell differentiation in CRMP2KI mice. Moreover, the transcriptome profile of CRMP2KI mice has been discussed wherein energy metabolism and neuronal pathways were found to be differentially regulated. Our results showed that CRMP2KI mice displayed improved SCI pathophysiology not only via microtubule stabilization in neurons, but also possibly via the whole metabolic system in the central nervous system, response changes in glial cells, and synapses. Taken together, we reveal new insights on SCI pathophysiology and the regenerative mechanism of central nervous system by the inhibition of CRMP2 phosphorylation at Ser522. All these experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee at Waseda University, Japan (2017-A027 approved on March 21, 2017; 2018-A003 approved on March 25, 2018; 2019-A026 approved on March 25, 2019).

Cortical Transplantation of Brain-Mimetic Glycosaminoglycan Scaffolds and Neural Progenitor Cells Promotes Vascular Regeneration and Functional Recovery after Ischemic Stroke in Mice.

Stroke causes significant mortality and morbidity. Currently, there are no treatments which can regenerate brain tissue lost to infarction. Neural progenitor cells (NPCs) are at the forefront of preclinical studies for regenerative stroke therapies. NPCs can differentiate into and replace neurons and promote endogenous recovery mechanisms such as angiogenesis via trophic factor production and release. The stroke core is hypothetically the ideal location for replacement of neural tissue since it is in situ and develops into a potential space where injections may be targeted with minimal compression of healthy peri-infarct tissue. However, the compromised perfusion and tissue degradation following ischemia create an inhospitable environment resistant to cellular therapy. Overcoming these limitations is critical to advancing cellular therapy. In this work, the therapeutic potential of mouse-induced pluripotent stem cell derived NPCs is tested encapsulated in a basic fibroblast growth factor (bFGF) binding chondroitin sulfate-A (CS-A) hydrogel transplanted into the infarct core in a mouse sensorimotor cortex mini-stroke model. It is shown that CS-A encapsulation significantly improves vascular remodeling, cortical blood flow, and sensorimotor behavioral outcomes after stroke. It is found these improvements are negated by blocking bFGF, suggesting that the sustained trophic signaling endowed by the CS-A hydrogel combined with NPC transplantation can promote tissue repair.

Сlass II histone deacetylases in the post-stroke recovery period-expression, cellular, and subcellular localization-promising targets for neuroprotection.

Histone deacetylases (HDAC) inhibitors can protect nerve cells after a stroke, but it is unclear which HDAC isoform is involved in this effect. We studied cellular and intracellular rearrangement of class II HDACs at late periods after photothrombotic infarct (PTI) in the mouse sensorimotor cortex in the tissue surrounding the ischemia core and in the corresponding region of the contralateral hemisphere. We observed a decrease in HDAC4 in cortical neurons and an increase in its nuclear translocation. HDAC6 expression in neurons was also increased. Moreover, HDAC6-positive cells had elevated apoptosis. Tubostatin A (Tub A)-induced decrease in the activity of HDAC6 restored acetylation of α-tubulin during the early poststroke recovery period and reduced apoptosis of nerve cells thus protecting the brain tissue. Selective inhibition of HDAC6 elevated expression of growth-associated protein-43 (GAP43), which remained high up to 14 days after stroke and promoted axogenesis and recovery from the PTI-induced neurological deficit. Selective HDAC6 inhibitor Tub A markedly reduced neuronal death and increased acetylation of α-tubulin and the level of GAP43. Thus, HDAC6 inhibition could be a promising strategy for modulation of brain recovery as it can increase the intensity and reduce the duration of reparation processes in the brain after stroke.

Transplantation of Directly Reprogrammed Human Neural Precursor Cells Following Stroke Promotes Synaptogenesis and Functional Recovery

Stroke is one of the leading causes of long-term disability. Cell transplantation is a promising strategy to treat stroke. We explored the efficacy of directly reprogrammed human neural precursor cell (drNPC) transplants to promote functional recovery in a model of focal ischemic stroke in the mouse sensorimotor cortex. We show that drNPCs express neural precursor cell markers and are neurally committed at the time of transplantation. Mice that received drNPC transplants recovered motor function, irrespective of transplant vehicle or recipient sex, and with no correlation to lesion volume or glial scarring. The majority of drNPCs found in vivo, at the time of functional recovery, remained undifferentiated. Notably, no correlation between functional recovery and long-term xenograft survival was observed, indicating that drNPCs provide therapeutic benefits beyond their survival. Furthermore, increased synaptophysin expression in transplanted brains suggests that drNPCs promote neuroplasticity through enhanced synaptogenesis. Our findings provide insight into the mechanistic underpinnings of drNPC-mediated recovery for stroke and support the notion that drNPCs may have clinical applications for stroke therapy.

Abstract TP264: Actin Reorganization is a Rapid and Reversible Adaptive Response by Neurons Exposed to Ischemic and Excitotoxic Injury in vitro and in vivo

In initial stages of ischemic injury, glutamate receptor hyperactivation mediates extensive neuronal cell death. Most of this initial death is due to cytotoxic edema, whereby sodium and chloride entry cause cell swelling. Early subcellular responses to neuronal edema are poorly understood. We observed that actin filaments (F-actin) undergo a dramatic reorganization within the somatodendritic domain of neurons exposed to ischemia and/or sublethal excitotoxicity in vivo and in vitro. Fluorescence imaging was performed on embryonic rat hippocampal neurons cultured for 21-days in vitro. “Ministrokes” were induced in vivo by photothrombosis of a single penetrating vessel in mouse sensorimotor cortex. Animals were fixed 4 or 6 hours after vessel occlusion. Fluorescence images were analyzed in infarct, peri-infarct, and contralateral regions. All experiments were repeated 3-4 times, and quantified in a blinded fashion In control tissue F-actin is concentrated within dendritic spines, with little F-actin in the dendrite shaft. Within 5 min of applying 50μM NMDA, F-actin is lost from spines (inducing spine shrinkage) and polymerizes into long filament bundles within the dendrite shaft and soma. A similar redistribution of actin occurs after oxygen/glucose deprivation in vitro and after stroke in vivo. In vitro these actin changes are reversible within 1-3 hours of transient NMDA exposure. Increased Ca2+ is necessary but not sufficient for iniduction. Conditions that reduce cytotoxic edema prevent actinification; conditions that promote cytotoxic edema induce actinfication. The actin nucleator inverted formin-2 (INF2) was found to mediate dendrite actinification. Pharmacological inhibition of formins but not Arp2/3, completely prevented actinification. Moreover, silencing of endogenous INF2 using shRNA prevented NMDA-induced actinification; overexpression of wildtype INF2 sensitized neurons to actinification. Silencing of INF2 rendered neurons more vulnerable to NMDA-induced cell death. Results indicate that ischemia-induced actin filament accumulation within the somatodendritic compartment is a pro-survival response that protects neurons from death induced by cell swelling.

Expression of Class IHistone Deacetylases in Ipsilateral and Contralateral Hemispheres after the Focal Photothrombotic Infarction in the Mouse Brain.

Histone acetylation and deacetylation are among the most important epigenetic processes that regulate gene expression. Nonselective inhibitors of histone deacetylases (HDAC) can protect brain cells during ischemia and stroke. However, which HDAC isoform is involved in this effect is unknown. Some isoforms of histone deacetylases (HDACs) protect brain cells after ischemia, whereas others can promote their death. Most studies consider early periods (1-24h) after stroke, whereas little is known on the involvement of HDACs during recovery after stroke. In this study, cellular and intracellular rearrangement of class I HDACs (HDAC1, HDAC2, HDAC3, HDAC8) was investigated at late periods after photothrombotic infarction (PTI) of the mouse sensorimotor cortex in intact tissue that surrounds the ischemia core, in the corresponding region of the contralateral hemisphere, and in the hippocampus. Each HDAC isoform had a specific pattern of expression and intracellular distribution in neurons and astrocytes at different periods after the ischemia. We did not observe ischemia-induced changes in the subcellular localization of HDACs under study. Three days after the PTI, the expression of HDAC2 was increased in neurons of the damaged hemisphere. The activity of HDAC2 and HDAC8 was elevated 7days after the ischemia both in neurons and astrocytes of the studied brain structures; the activity of HDAC8 was also increased 14days after the ischemia. It is notable that the expression of class I HDACs in the intact hemisphere changes in the same way as their expression in the living tissue of the damaged hemisphere. HDAC1 was found both in the nuclei and cytoplasm of the brain cells; HDAC2 was predominantly localized in the nuclei, and HDAC8 was predominantly observed in the cytoplasm. This in addition to the regulation of gene transcription indicates nontranscriptional activity of HDAC1 and HDAC8 during recovery of the brain tissue after the ischemia. HDAC2 and HDAC8 were identified as potential mediators in an early recovery period after stroke, suggesting that selective inhibitors and activators of HDACs can be considered for therapeutic approaches in this period.

Optogenetic Stimulation of Cortex to Map Evoked Whisker Movements in Awake Head-Restrained Mice

Whisker movements are used by rodents to touch objects in order to extract spatial and textural tactile information about their immediate surroundings. To understand the mechanisms of such active sensorimotor processing it is important to investigate whisker motor control. The activity of neurons in the neocortex affects whisker movements, but many aspects of the organization of cortical whisker motor control remain unknown. Here, we filmed whisker movements evoked by sequential optogenetic stimulation of different locations across the left dorsal sensorimotor cortex of awake head-restrained mice. Whisker movements were evoked by optogenetic stimulation of many regions in the dorsal sensorimotor cortex. Optogenetic stimulation of whisker sensory barrel cortex evoked retraction of the contralateral whisker after a short latency, and a delayed rhythmic protraction of the ipsilateral whisker. Optogenetic stimulation of frontal cortex evoked rhythmic bilateral whisker protraction with a longer latency compared to stimulation of sensory cortex. Compared to frontal cortex stimulation, larger amplitude bilateral rhythmic whisking in a less protracted position was evoked at a similar latency by stimulating a cortical region posterior to Bregma and close to the midline. These data suggest that whisker motor control might be broadly distributed across the dorsal mouse sensorimotor cortex. Future experiments must investigate the complex neuronal circuits connecting specific cell-types in various cortical regions with the whisker motor neurons located in the facial nucleus.

Voltage-sensitive dye imaging of mouse neocortex during a whisker detection task.

Sensorimotor processing occurs in a highly distributed manner in the mammalian neocortex. The spatiotemporal dynamics of electrical activity in the dorsal mouse neocortex can be imaged using voltage-sensitive dyes (VSDs) with near-millisecond temporal resolution and [Formula: see text] spatial resolution. Here, we trained mice to lick a water reward spout after a 1-ms deflection of the C2 whisker, and we imaged cortical dynamics during task execution with VSD RH1691. Responses to whisker deflection were highly dynamic and spatially highly distributed, exhibiting high variability from trial to trial in amplitude and spatiotemporal dynamics. We differentiated trials based on licking and whisking behavior. Hit trials, in which the mouse licked after the whisker stimulus, were accompanied by overall greater depolarization compared to miss trials, with the strongest hit versus miss differences being found in frontal cortex. Prestimulus whisking decreased behavioral performance by increasing the fraction of miss trials, and these miss trials had attenuated cortical sensorimotor responses. Our data suggest that the spatiotemporal dynamics of depolarization in mouse sensorimotor cortex evoked by a single brief whisker deflection are subject to important behavioral modulation during the execution of a simple, learned, goal-directed sensorimotor transformation.

Sulforhodamine 101, a widely used astrocyte marker, can induce cortical seizure-like activity at concentrations commonly used

Sulforhodamine 101 (SR101) is a preferential astrocyte marker widely used in 2-photon microscopy experiments. Here we show, that topical loading of two commonly used SR101 concentrations, 100 μM and 250 μM when incubated for 10 min, can induce seizure-like local field potential (LFP) activity in both anaesthetized and awake mouse sensori-motor cortex. This cortical seizure-like activity develops in less than ten minutes following topical loading, and when applied longer, these neuronal discharges reliably evoke contra-lateral hindlimb muscle contractions. Short duration (<1 min) incubation of 100 μM and 250 μM SR101 or application of lower concentrations 25 μM and 50 μM of SR101, incubated for 30 and 20 min, respectively, did not induce abnormal LFP activity in sensori-motor cortex, but did label astrocytes, and may thus be considered more appropriate concentrations for in vivo astrocyte labeling. In addition to label astrocytes SR101 may, at 100 μM and 250 μM, induce abnormal neuronal activity and interfere with cortical circuit activity. SR101 concentration of 50 μM or lower did not induce abnormal neuronal activity. We advocate that, to label astrocytes with SR101, concentrations no higher than 50 μM should be used for in vivo experiments.

Brief anesthesia, but not voluntary locomotion, significantly alters cortical temperature.

Changes in brain temperature can alter electrical properties of neurons and cause changes in behavior. However, it is not well understood how behaviors, like locomotion, or experimental manipulations, like anesthesia, alter brain temperature. We implanted thermocouples in sensorimotor cortex of mice to understand how cortical temperature was affected by locomotion, as well as by brief and prolonged anesthesia. Voluntary locomotion induced small (∼ 0.1 °C) but reliable increases in cortical temperature that could be described using a linear convolution model. In contrast, brief (90-s) exposure to isoflurane anesthesia depressed cortical temperature by ∼ 2 °C, which lasted for up to 30 min after the cessation of anesthesia. Cortical temperature decreases were not accompanied by a concomitant decrease in the γ-band local field potential power, multiunit firing rate, or locomotion behavior, which all returned to baseline within a few minutes after the cessation of anesthesia. In anesthetized animals where core body temperature was kept constant, cortical temperature was still > 1 °C lower than in the awake animal. Thermocouples implanted in the subcortex showed similar temperature changes under anesthesia, suggesting these responses occur throughout the brain. Two-photon microscopy of individual blood vessel dynamics following brief isoflurane exposure revealed a large increase in vessel diameter that ceased before the brain temperature significantly decreased, indicating cerebral heat loss was not due to increased cerebral blood vessel dilation. These data should be considered in experimental designs recording in anesthetized preparations, computational models relating temperature and neural activity, and awake-behaving methods that require brief anesthesia before experimental procedures.

Emergence of Adaptive Computation by Single Neurons in the Developing Cortex

Adaptation is a fundamental computational motif in neural processing. To maintain stable perception in the face of rapidly shifting input, neural systems must extract relevant information from background fluctuations under many different contexts. Many neural systems are able to adjust their input-output properties such that an input's ability to trigger a response depends on the size of that input relative to its local statistical context. This "gain-scaling" strategy has been shown to be an efficient coding strategy. We report here that this property emerges during early development as an intrinsic property of single neurons in mouse sensorimotor cortex, coinciding with the disappearance of spontaneous waves of network activity, and can be modulated by changing the balance of spike-generating currents. Simultaneously, developing neurons move toward a common intrinsic operating point and a stable ratio of spike-generating currents. This developmental trajectory occurs in the absence of sensory input or spontaneous network activity. Through a combination of electrophysiology and modeling, we demonstrate that developing cortical neurons develop the ability to perform nearly perfect gain scaling by virtue of the maturing spike-generating currents alone. We use reduced single neuron models to identify the conditions for this property to hold.

Altered resting-state functional connectivity after cortical spreading depression in mice

Cortical spreading depression (CSD) underlies some neurological disorders. Previous imaging work suggests that CSD is associated with functional and structural alterations in the cerebral cortex. However, the changes in cortical functional network following CSD are poorly understood. The present study examines the changes in resting-state function connectivity (RSFC) of the mouse sensorimotor cortex after the onset of CSD by using optical intrinsic signal imaging. Our results show that RSFC between ipsilateral sensorimotor cortex (the cortex where CSD spreads) and contralateral sensorimotor cortex (the cortex where CSD does not spread) was significantly reduced after CSD. Moreover, a marked connectivity increase was found after CSD not only within contralateral somatosensory cortex and contralateral motor cortex themselves, but also between contralateral somatosensory cortex and contralateral motor cortex. Amplitude of low-frequency fluctuation (ALFF) analysis revealed an increase in ALFF in the ipsilateral cortex but a decrease in the contralateral cortex after CSD, indicating different effects of CSD on the neural activity in the ipsilateral and contralateral sensorimotor cortexes. These results suggest that CSD would alter the RSFC in the sensorimotor cortexes, and functional connectivity analysis may help to understand the effect of CSD on the cerebral functional network.

Interneuron progenitors attenuate the power of acute focal ictal discharges.

Interneuron progenitors from the embryonic medial ganglionic eminence (MGE) can migrate, differentiate, and enhance local inhibition after transplantation into the postnatal cortex. Whether grafted MGE cells can reduce ictal activity in adult neocortex is unknown. We transplanted live MGE or killed cells (control) from pan green fluorescent protein expressing mice into adult mouse sensorimotor cortex. One week, 2 and 1/2 weeks, or 6 to 8 weeks after transplant, acute focal ictal epileptiform discharges were induced by injection of 4-aminopyridine (4-AP) 2 mm away from the site of transplantation. The local field potential of the events was recorded with 2 electrodes, 1 located in the 4-AP focus and the other 1 in the transplantation site. In all control groups and in the 1-week live cell transplant, 4-AP ictal discharges revealed no attenuation in power and duration from the onset site to the site of transplantation. However, 2.5 or 6 ~ 8 weeks after MGE transplants, there was a dramatic decrease in local field potential power at the MGE transplanted site with little decrease in ictal duration. Surprisingly, there was no relationship between grafted cell distribution or density and the degree of attenuation. As remarkably low graft densities still significantly reduced discharge power, these data provide further support for the therapeutic potential of interneuron precursor transplants in the treatment of neocortical epilepsy.

Origins of contrast gain control in isolated cortical neurons: deriving the code from the dynamics

Origins of contrast gain control in isolated cortical neurons: deriving the code from the dynamics

Sensorimotor behavioral effects of endothelin-1 induced small cortical infarcts in C57BL/6 mice

Mouse models have not paralleled rat models of stroke in advances in sensitive, species appropriate measures of neurological and behavioral recovery. Most available tests of mouse sensorimotor function are adaptations of those originally developed in rats and may not be as sensitive in detecting behavioral deficits after small cortical lesions in mice. Our purpose was to test the use of a vasoconstricting peptide, endothelin-1 (ET-1), to produce focal infarcts of the mouse sensorimotor cortex and to establish a behavioral test battery sensitive to resulting sensorimotor deficits. Young adult (3–5-month-old) male C57BL/6 mice received intracortical infusions of ET-1 that produced unilateral lesions of the forelimb region of the sensorimotor cortex, intracortical infusions of sterile saline, or sham surgeries. Pre-operatively and at various time points over 3 weeks post-surgery, they were administered a test battery that included measures of sensorimotor asymmetry (Corner and Bilateral Tactile Stimulation Tests), coordinated forepaw use (Cylinder and Ladder Rung Tests), and dexterous forepaw function (Pasta Matrix Reaching Test). ET-1 infusions resulted in consistently placed, focal cortical infarcts and forelimb impairments as measured with the Ladder Rung, Bilateral Tactile Stimulation, and Pasta Matrix Reaching Tests. On the Bilateral Tactile Stimulation and Pasta Matrix Reaching Tests, impairments persisted throughout the time span of observation (26 days). These results support ET-1 as a viable option for creating small, reproducible lesions of anatomical subregions in the mouse neocortex that result in lasting functional impairments in the forelimb, as observed with sufficiently sensitive measures.

Gene, Cell, and Axon Changes in the Familial Amyotrophic Lateral Sclerosis Mouse Sensorimotor Cortex

Lower motoneuron abnormalities have been extensively documented in the murine model of familial amyotrophic lateral sclerosis, whereas information on corticospinal neurons in these mice is very limited. We investigated 1) mRNA levels of inflammation-related molecules in the deep layers in which corticospinal neurons reside, 2) corticospinal neurons labeled from tracer injections in the corticospinal tract at the cervical level, 3) axonal damage revealed by beta-amyloid precursor protein accumulation, and 4) glial cell activation in the sensorimotor cortex of presymptomatic and end-stage superoxide dismutase (SOD)-1 (G93A) mice. We demonstrated induction of inflammatory gene transcripts in the deep layers, early and progressive shrinkage of corticospinal cell bodies and activation of surrounding astrocytes and microglia with upregulation of major histocompatibility complex class I antigen. Accumulation of beta-amyloid precursor protein in proximal axonal swellings indicating axonal injury was also evident at the terminal stage in the motor cortex and internal capsule. Glial and axon changes were not observed elsewhere in the cortex. These data reveal that the entire motor circuit is affected in this murine amyotrophic lateral sclerosis model as it is in human amyotrophic lateral sclerosis. Sensorimotor cortical inflammation and progressive corticospinal cell body and fiber damage may reflect transsynaptic signaling of damage from lower motoneurons.

Voltage-gated currents, dye and electrical coupling in the embryonic mouse neocortex.

We measured dye coupling, electrical coupling, and voltage-gated currents using whole-cell voltage clamp in slices of mouse sensorimotor cortex at embryonic day 14 (E14). As in rat ventricular zone (VZ), cells of the VZ were extensively dye coupled, often in clusters of >100 cells. In mouse VZ, however, cells were much less electrically coupled, making measurement of voltage-gated currents more accurate. All VZ cells expressed delayed K(+) currents (I(K)), and 30%, including morphologically identified radial glia, also expressed inward Na(+) currents (I(Na)). This fraction is consistent with I(Na) expression being an early event following cell cycle exit. Intermediate zone (IZ) cells also expressed I(K) and I(Na). Na(+) current amplitude distributions indicated three populations of IZ cells: those without I(Na), those with I(Na) similar in amplitude to VZ cells, and those with I(Na) being almost 10 times larger than in VZ cells. Cells of the cortical plate (CP) expressed both I(K) and I(Na), with I(Na) being almost 10-fold larger than in VZ cells. No cell in any zone expressed detectable hyperpolarization-activated currents. Our data suggest that the distribution and density of I(Na) may be related to early events of cell cycle exit and migration.