Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

Patients' Trust in Artificial Intelligence-based Decision-making for Localized Prostate Cancer: Results from a Prospective Trial.

BACKGROUND: Artificial intelligence (AI) has the potential to enhance diagnostic accuracy and improve treatment outcomes. However, AI integration into clinical workflows and patient perspectives remain unclear. OBJECTIVE: To determine patients' trust in AI and their perception of urologists relying on AI, and future diagnostic and therapeutic AI applications for patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective trial was conducted involving patients who received diagnostic or therapeutic interventions for prostate cancer (PC). INTERVENTION: Patients were asked to complete a survey before magnetic resonance imaging, prostate biopsy, or radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was patient trust in AI. Secondary outcomes were the choice of AI in treatment settings and traits attributed to AI and urologists. RESULTS AND LIMITATIONS: Data for 466 patients were analyzed. The cumulative affinity for technology was positively correlated with trust in AI (correlation coefficient 0.094; p = 0.04), whereas patient age, level of education, and subjective perception of illness were not (p > 0.05). The mean score (± standard deviation) for trust in capability was higher for physicians than for AI for responding in an individualized way when communicating a diagnosis (4.51 ± 0.76 vs 3.38 ± 1.07; mean difference [MD] 1.130, 95% confidence interval [CI] 1.010-1.250; t924 = 18.52, p < 0.001; Cohen's d = 1.040) and for explaining information in an understandable way (4.57 ± vs 3.18 ± 1.09; MD 1.392, 95% CI 1.275-1.509; t921 = 27.27, p < 0.001; Cohen's d = 1.216). Patients stated that they had higher trust in a diagnosis made by AI controlled by a physician versus AI not controlled by a physician (4.31 ± 0.88 vs 1.75 ± 0.93; MD 2.561, 95% CI 2.444-2.678; t925 = 42.89, p < 0.001; Cohen's d = 2.818). AI-assisted physicians (66.74%) were preferred over physicians alone (29.61%), physicians controlled by AI (2.36%), and AI alone (0.64%) for treatment in the current clinical scenario. CONCLUSIONS: Trust in future diagnostic and therapeutic AI-based treatment relies on optimal integration with urologists as the human-machine interface to leverage human and AI capabilities. PATIENT SUMMARY: Artificial intelligence (AI) will play a role in diagnostic decisions in prostate cancer in the future. At present, patients prefer AI-assisted urologists over urologists alone, AI alone, and AI-controlled urologists. Specific traits of AI and urologists could be used to optimize diagnosis and treatment for patients with prostate cancer.

Soluble amyloid-ß precursor peptide does not regulate GABAB receptor activity.

Amyloid-ß precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release, or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.

GABAB receptor subtypes differentially regulate thalamic spindle oscillations.

Following the discovery of GABAB receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABAB receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABAB1a, GABAB1b and GABAB2 form two heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K+ channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABAB(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABAB(1a,2) receptors function as heteroreceptors and inhibit glutamate release. Both GABAB(1a,2) and GABAB(1b,2) receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABAB receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABAB receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABAB(1a,2) and GABAB(1b,2) receptors on spindle oscillations. We found that selectively GABAB(1a,2) heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABAB(1b,2) receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABAB(1a,2) and GABAB(1b,2) receptors. This article is part of the "Special Issue Dedicated to Norman G. Bowery".

Sleep Spindles as Facilitators of Memory Formation and Learning.

Over the past decades important progress has been made in understanding the mechanisms of sleep spindle generation. At the same time a physiological role of sleep spindles is starting to be revealed. Behavioural studies in humans and animals have found significant correlations between the recall performance in different learning tasks and the amount of sleep spindles in the intervening sleep. Concomitant neurophysiological experiments showed a close relationship between sleep spindles and other sleep related EEG rhythms as well as a relationship between sleep spindles and synaptic plasticity. Together, there is growing evidence from several disciplines in neuroscience for a participation of sleep spindles in memory formation and learning.

Telemental Health Training, Team Building, and Workforce Development in Cultural Context: The Hawaii Experience.

OBJECTIVE: The goal of the University of Hawaii (UH) child and adolescent psychiatry telemental health (TMH) program is to train child and adolescent psychiatry fellows to provide behavioral health services for the children of Hawaii and the Pacific Islands in the cultural context of their rural communities using interactive videoteleconferencing (IVTC). The training experience balances learning objectives with community service. Learning objectives include: Understanding mental health disparities in rural communities, leveraging community resources in ongoing treatment, providing culturally effective care, and improving health care access and delivery through TMH service research and evaluation. METHODS: We describe the UH experience. Several UH faculty are experienced with IVTC technology. They are triple-board trained, are recognized for their research in program evaluation and mental health disparities, and are committed to serving Hawaii's rural communities. We demonstrate the role of TMH in linking children and their families living in rural communities with multiple mental health treatment providers. The service-learning curriculum and a unique collaboration with Mayo Clinic provide the opportunity to examine the role of TMH in global service, and training, education, and research. RESULTS: TMH provides direct services to patients and consultation on Hawaii Island and Maui County. The collaboration with the Mayo Clinic brings further consultation in complex diagnostics, pharmacogenomics, and cross-cultural psychiatry. A curriculum provides trainees experience with IVTC with the goal of potential recruitment to underserved rural communities. The TMH program at UH is unique in its team building and workforce development by joining multiple entities through IVTC and translating expertise from the Mayo Clinic to rural communities, and strengthening collaboration with local child and adolescent psychiatrists, and primary care and other mental health providers. CONCLUSIONS: The UH psychiatry program is a model program to develop an expert mental health workforce in cultural context for children living in rural communities.

A Gaze Independent Brain-Computer Interface Based on Visual Stimulation through Closed Eyelids.

A classical brain-computer interface (BCI) based on visual event-related potentials (ERPs) is of limited application value for paralyzed patients with severe oculomotor impairments. In this study, we introduce a novel gaze independent BCI paradigm that can be potentially used for such end-users because visual stimuli are administered on closed eyelids. The paradigm involved verbally presented questions with 3 possible answers. Online BCI experiments were conducted with twelve healthy subjects, where they selected one option by attending to one of three different visual stimuli. It was confirmed that typical cognitive ERPs can be evidently modulated by the attention of a target stimulus in eyes-closed and gaze independent condition, and further classified with high accuracy during online operation (74.58% ± 17.85 s.d.; chance level 33.33%), demonstrating the effectiveness of the proposed novel visual ERP paradigm. Also, stimulus-specific eye movements observed during stimulation were verified as reflex responses to light stimuli, and they did not contribute to classification. To the best of our knowledge, this study is the first to show the possibility of using a gaze independent visual ERP paradigm in an eyes-closed condition, thereby providing another communication option for severely locked-in patients suffering from complex ocular dysfunctions.

Amyloid-ß Impairs Synaptic Inhibition via GABA(A) Receptor Endocytosis.

Amyloid ß (Aß) is thought to play an important role in the pathogenesis of Alzheimer's disease. Aß may exert its neurotoxic effects via multiple mechanisms and in particular through degradation of excitatory synaptic transmission associated with impaired synaptic plasticity. In contrast, much less is known about Aß effects at inhibitory synapses. This study investigates the impact of acute Aß1-42 application on GABAergic synaptic transmission in rat somatosensory cortex in vitro. Whole-cell voltage-clamp recordings were obtained from layer V pyramidal cells, and monosynaptic GABA(A) receptor-mediated IPSCs were elicited. Bath-applied Aß (1 µm) depressed the IPSCs on average to 60% of control, whereas a reversed sequence control peptide was ineffective. Paired-pulse stimuli indicated a postsynaptic site of action. This was further corroborated by a decreased postsynaptic responsiveness to local puffs of the GABAA receptor agonist isoguvacine. The Aß-induced IPSC decline could be prevented with intracellular applications of p4, a blocker of GABA(A) receptor internalization. It is concluded that Aß weakens synaptic inhibition via downregulation of GABA(A) receptors.

Subthreshold delta-frequency resonance in thalamic reticular neurons.

The thalamic reticular nucleus (nRt) is an assembly of GABAergic projection neurons that participate in the generation of brain rhythms during synchronous sleep and absence epilepsy. NRt cells receive inhibitory and excitatory synaptic inputs, and are endowed with an intricate set of intrinsic conductances. However, little is known about how intrinsic and synaptic properties interact to generate rhythmic discharges in these neurons. In order to better understand this interaction, I studied the subthreshold responses of nRt cells to time-varying inputs. Patch-clamp recordings were performed in acute slices of rat thalamus (postnatal days 12-21). Sinusoidal current waveforms of linearly changing frequencies were injected into the soma, and the resulting voltage oscillations were recorded. At the resting membrane potential, the impedance profile showed a characteristic resonance at 1.7 Hz. The relative strength of the resonance was 1.2, and increased with membrane hyperpolarization. Small suprathreshold current injections led to preferred spike generation at the resonance frequency. Bath application of ZD7288 or Cs(+) , inhibitors of the hyperpolarization-activated cation current (Ih ), transformed the resonance into low-pass behaviour, whereas the T-channel blockers mibefradil and Ni(2+) decreased the strength of the resonance. It is concluded that nRt cells have an Ih -mediated intrinsic frequency preference in the subthreshold voltage range that favours action potential generation in the delta-frequency band.

Removal of synaptic Ca²+-permeable AMPA receptors during sleep.

There is accumulating evidence that sleep contributes to memory formation and learning, but the underlying cellular mechanisms are incompletely understood. To investigate the impact of sleep on excitatory synaptic transmission, we obtained whole-cell patch-clamp recordings from layer V pyramidal neurons in acute slices of somatosensory cortex of juvenile rats (postnatal days 21-25). In animals after the dark period, philanthotoxin 74 (PhTx)-sensitive calcium-permeable AMPA receptors (CP-AMPARs) accounted for ∼25% of total EPSP size, and current-voltage (I-V) relationships of the underlying EPSCs showed inward rectification. In contrast, in similar experiments after the light period, EPSPs were PhTx insensitive with linear I-V characteristics, indicating that CP-AMPARs were less abundant. Combined EEG and EMG recordings confirmed that slow-wave sleep-associated delta wave power peaked at the onset of the more quiescent, lights-on phase of the cycle. Subsequently, we show that burst firing, a characteristic action potential discharge mode of layer V pyramidal neurons during slow-wave sleep has a dual impact on synaptic AMPA receptor composition: repetitive burst firing without synaptic stimulation eliminated CP-AMPARs by activating serine/threonine phosphatases. Additionally, repetitive burst-firing paired with EPSPs led to input-specific long-term depression (LTD), affecting Ca(2+) impermeable AMPARs via protein kinase C signaling. In agreement with two parallel mechanisms, simple bursts were ineffective after the light period but paired bursts induced robust LTD. In contrast, incremental LTD was generated by both conditioning protocols after the dark cycle. Together, our results demonstrate qualitative changes at neocortical glutamatergic synapses that can be induced by discharge patterns characteristic of non-rapid eye movement sleep.

Functional mapping of GABA(B)-receptor subtypes in the thalamus.

The thalamus plays an important role in attention mechanisms and the generation of brain rhythms. gamma-Aminobutyric acid type B (GABA(B)) receptors are known to regulate the main output neurons of the thalamus, the thalamocortical relay (TCR) cells. However, the contributions of the two predominant GABA(B)-receptor subtypes, GABA(B(1a,2)) and GABA(B(1b,2)), to the control of TCR cell activity are unknown. Here, we used genetic and electrophysiological methods to investigate subtype-specific GABA(B) effects at the inputs to TCR cells. We found that mainly GABA(B(1a,2)) receptors inhibit the release of glutamate from corticothalamic fibers impinging onto TCR cells. In contrast, both GABA(B(1a,2)) and GABA(B(1b,2)) receptors efficiently inhibit the release of GABA from thalamic reticular nucleus (TRN) neurons onto TCR neurons. Likewise, both GABA(B(1a,2)) and GABA(B(1b,2)) receptors efficiently activate somatodendritic K(+) currents in TCR cells. In summary, our data show that GABA(B(1b,2)) receptors cannot compensate for the absence of GABA(B(1a,2)) receptors at glutamatergic inputs to TCR cells. This shows that the predominant association of GABA(B(1a,2)) receptors with glutamatergic terminals is a feature that is preserved at several brain synapses. Furthermore, our data indicate that the cognitive deficits observed with mice lacking GABA(B(1a,2)) receptors could to some extent relate to attention deficits caused by disinhibited release of glutamate onto TCR neurons.

GABA(B) receptors: synaptic functions and mechanisms of diversity.

GABA(B) receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the mammalian central nervous system. They are implicated in a variety of neurological and psychiatric disorders. With the cloning of GABA(B) receptors ten years ago, substantial progress was made in our understanding of this receptor system. Here, we review current concepts of synaptic GABA(B) functions and present the evidence that points to specific roles for receptor subtypes. We discuss ultrastructural studies revealing that most GABA(B) receptors are located remote from GABAergic terminals, which raises questions as to when such receptors become activated. Finally, we provide possible explanations for the perplexing situation that GABA(B) receptor subtypes that have indistinguishable properties in vitro generate distinct GABA(B) responses in vivo.

Cellular mechanisms of burst firing-mediated long-term depression in rat neocortical pyramidal cells.

During wakefulness and sleep, neurons in the neocortex emit action potentials tonically or in rhythmic bursts, respectively. However, the role of synchronized discharge patterns is largely unknown. We have recently shown that pairings of excitatory postsynaptic potentials (EPSPs) and action potential bursts or single spikes lead to long-term depression (burst-LTD) or long-term potentiation, respectively. In this study, we elucidate the cellular mechanisms of burst-LTD and characterize its functional properties. Whole-cell patch-clamp recordings were obtained from layer V pyramidal cells in somatosensory cortex of juvenile rats in vitro and composite EPSPs and EPSCs were evoked extracellularly in layers II/III. Repetitive burst-pairings led to a long-lasting depression of EPSPs and EPSCs that was blocked by inhibitors of metabotropic glutamate group 1 receptors, phospholipase C, protein kinase C (PKC) and calcium release from the endoplasmic reticulum, and that required an intact machinery for endocytosis. Thus, burst-LTD is induced via a Ca2+- and phosphatidylinositol-dependent activation of PKC and expressed through phosphorylation-triggered endocytosis of AMPA receptors. Functionally, burst-LTD is inversely related to EPSP size and bursts dominate single spikes in determining the sign of synaptic plasticity. Thus burst-firing constitutes a signal by which coincident synaptic inputs are proportionally downsized. Overall, our data thus suggest a mechanism by which synaptic weights can be reconfigured during non-rapid eye movement sleep.

Pattern-specific associative long-term potentiation induced by a sleep spindle-related spike train.

Spindles are non-rapid eye movement (non-REM) sleep EEG rhythms (7-14 Hz) that occur independently or in association with slow oscillations (0.6-0.8 Hz). Despite their proposed function in learning and memory, their role in synaptic plasticity is essentially unknown. We studied the ability of a neuronal firing pattern underlying spindles in vivo to induce synaptic plasticity in neocortical pyramidal cells in vitro. A spindle stimulation pattern (SSP) was extracted from a slow oscillation upstate that was recorded in a cat anesthetized with ketamine-xylazine, which is known to induce a sleep-like state. To mimic the recurrence of spindles grouped by the slow oscillation, the SSP was repeated every 1.5 s (0.6 Hz). Whole-cell patch-clamp recordings were obtained from layer V pyramidal cells of rat somatosensory cortex with infrared videomicroscopy, and composite EPSPs were evoked within layers II-III. Trains of EPSPs and action potentials simultaneously triggered by the SSP induced an NMDA receptor-dependent short-term potentiation (STP) and an L-type Ca2+ channel-dependent long-term potentiation (LTP). The number of spindle sequences affected the amount of STP-LTP. In contrast, spindle trains of EPSPs alone led to long-term depression. LTP was not consistently induced by a regular firing pattern, a mirrored SSP, or a randomized SSP; however, a synthetic spindle pattern consisting of repetitive spike bursts at 10 Hz reliably induced STP-LTP. Our results show that spindle-associated spike discharges are efficient in modifying excitatory neocortical synapses according to a Hebbian rule. This is in support of a role for sleep spindles in memory consolidation.

Firing mode-dependent synaptic plasticity in rat neocortical pyramidal neurons.

Pyramidal cells in the mammalian neocortex can emit action potentials either as series of individual spikes or as distinct clusters of high-frequency bursts. However, why two different firing modes exist is largely unknown. In this study, we report that in layer V pyramidal cells of the rat somatosensory cortex, in vitro associations of EPSPs with spike bursts delayed by +10 msec led to long-term synaptic depression (LTD), whereas pairings with individual action potentials at the same delay induced long-term potentiation. EPSPs were evoked extracellularly in layer II-III and recorded intracellularly in layer V neurons with the whole-cell or nystatin-based perforated patch-clamp technique. Bursts were evoked with brief somatic current injections, resulting in three to four action potentials with interspike frequencies of approximately 200 Hz, characteristic of intrinsic burst firing. Burst-firing-associated LTD (Burst-LTD) was robust over a wide range of intervals between -100 and +200 msec, and depression was maximal (approximately 50%) for closely spaced presynaptic and postsynaptic events. Burst-LTD was associative and required concomitant activation of low voltage-activated calcium currents and metabotropic glutamate receptors. Conversely, burst-LTD was resistant to blockade of NMDA receptors or inhibitory synaptic potentials. Burst-LTD was also inducible at already potentiated synapses. We conclude that intrinsic burst firing represents a signal for resetting excitatory synaptic weights.

Electrophysiological characterization of synaptic connections between layer VI cortical cells and neurons of the nucleus reticularis thalami in juvenile rats.

Corticothalamic (CT) feedback projections to the thalamus outnumber sensory inputs from the periphery by orders of magnitude. However, their functional role remains elusive. CT projections may directly excite thalamic relay cells or indirectly inhibit them via excitation of the nucleus reticularis thalami (nRT), a nuclear formation composed entirely of gamma-aminobutyric acidergic neurons. The relative strengths of these two pathways will ultimately control the effects of CT projections on the output of thalamic relay cells. However, corticoreticular synapses have not yet been fully physiologically characterized. Here, local stimulation of layer VI cells by focal application of K+ or AMPA elicited excitatory postsynaptic potentials in nRT neurons with a mean peak amplitude of 2.4 +/- 0.1 mV (n = 75, mean +/- SEM), a mean rise time (10-90%) of 0.74 +/- 0.03 ms and a weighted decay time constant of 11 +/- 0.3 ms. A pharmacological profile of responses was drawn in both current-clamp and voltage-clamp modes, showing the presence of a small N-methyl-d-aspartate receptor-dependent component at depolarized potentials. In two pairs of synaptically coupled layer VI cell-nRT neuron, moderate rates of transmission failures were observed while the latencies were above 5 ms in both cases. Our results indicate that the corticoreticular pathway fulfills the criteria for 'modulatory' inputs and is temporally restricted. We suggest that it may be involved in coincidence detection of convergent corticoreticular signals.

Differential arithmetic of shunting inhibition for voltage and spike rate in neocortical pyramidal cells.

The main inhibitory neurotransmitter in the mammalian forebrain is gamma-amino butyric acid (GABA), which acts through A and B type receptors. GABAA receptors mediate inhibition via an increase in membrane conductance (shunting) and/or membrane potential hyperpolarization. Shunting inhibition is thought to decrease the gain between neural input and output, and thus to act as a divisor, but may do so only below the spike threshold. To investigate the role of shunting inhibition in neocortical neurons, whole-cell patch-clamp recordings were obtained from layer V pyramidal cells of somatosensory cortex in juvenile rats. Sub- and suprathreshold voltage responses were elicited by somatic step current injections and a shunting conductance was generated via a dynamic clamp. Increasing the dynamic clamp shunting conductance led to a parallel shift of the current-discharge curves and a reduced slope of the current-voltage relationship, i.e. a decrease of neural gain. Selective activation of GABAAA receptors with the competitive agonist isoguvacine or rises of endogenous GABA with the specific reuptake blocker nipecotic acid led to a proportional decrease of subthreshold membrane voltage, but a constant offset of discharge rates, thus acting like a shunting conductance. Similarly, isoguvacine and nipecotic acid decreased the gain of excitatory postsynaptic potentials. In all three experimental conditions, shunting inhibition divisively affected subthreshold voltages, while the time-averaged suprathreshold membrane potential was offset by a constant amount. I conclude that shunting inhibition in pyramidal cells has a dual impact on neural output: it is divisive for subthreshold voltages but subtractive for spike frequencies.

Strong, reliable and precise synaptic connections between thalamic relay cells and neurones of the nucleus reticularis in juvenile rats.

The thalamic reticular nucleus (nRT) is composed entirely of GABAergic inhibitory neurones that receive input from pyramidal cortical neurones and excitatory relay cells of the ventrobasal complex of the thalamus (VB). It plays a major role in the synchrony of thalamic networks, yet the synaptic connections it receives from VB cells have never been fully physiologically characterised. Here, whole-cell current-clamp recordings were obtained from 22 synaptically connected VB-nRT cell pairs in slices of juvenile (P14-20) rats. At 34-36 degrees C, single presynaptic APs evoked unitary EPSPs in nRT cells with a peak amplitude of 7.4 +/- 1.5 mV (mean +/- S.E.M.) and a decay time constant of 15.1 +/- 0.9 ms. Only four out of 22 pairs showed transmission failures at a mean rate of 6.8 +/- 1.1 %. An NMDA receptor (NMDAR)-mediated component was significant at rest and subsequent EPSPs in a train were depressed. Only one out of 14 pairs tested was reciprocally connected; the observed IPSPs in the VB cell had a peak amplitude of 0.8 mV and were completely abolished in the presence of 10 microM bicuculline. Thus, synaptic connections from VB cells to nRT neurones are mainly 'drivers', while a small subset of cells form closed disynaptic loops.

Dendritic resonance in rat neocortical pyramidal cells.

Dendritic integration of synaptic signals is likely to be an important process by which nerve cells encode synaptic input into spike output. However, the response properties of dendrites to time-varying inputs are largely unknown. Here, I determine the transfer impedance of the apical dendrite in layer V pyramidal cells by dual whole cell patch-clamp recordings in slices of rat somatosensory cortex. Sinusoidal current waveforms of linearly changing frequencies (0.1-25 Hz) were alternately injected into the soma or apical dendrite and the resulting voltage oscillations recorded by the second electrode. Dendrosomatic and somatodendritic transfer impedances were calculated by Fourier analysis. At near physiological temperatures (T approximately 35 degrees C), the transfer impedance had a maximal magnitude at low frequencies (f(res) approximately 6 Hz). In addition, voltage led current up to approximately 3 Hz, followed by a current lead over voltage at higher frequencies. Thus the transfer impedance of the apical dendrite is characterized by a low-frequency resonance. The frequency of the resonance was voltage dependent, and its strength increased with dendritic distance. The resonance was completely abolished by the I(h) channel blocker ZD 7288. Dendrosomatic and somatodendritic transfer properties of the apical dendrite were independent of direction or amplitude of the input current, and the responses of individual versus distributed inputs were additive, thus implying linearity. For just threshold current injections, action potentials were generated preferentially at the resonating frequency. I conclude that due to the interplay of a sag current (I(h)) with the membrane capacitance, layer V pyramids can act as linear band-pass filters with a frequency preference in the theta frequency band.