Paired-pulse Depression Research Articles

Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity.

Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. Slc4a10 knockout (KO) mice have collapsed brain ventricles and display an increased seizure threshold, while heterozygous deletions in man have been associated with idiopathic epilepsy and other neurological symptoms. To further characterize the role of Slc4a10 for network excitability, we compared input-output relations as well as short and long term changes of evoked field potentials in Slc4a10 KO and wildtype (WT) mice. While responses of CA1 pyramidal neurons to stimulation of Schaffer collaterals were increased in Slc4a10 KO mice, evoked field potentials did not differ between genotypes in the stratum radiatum or the neocortical areas analyzed. Paired pulse facilitation was diminished in the hippocampus upon disruption of Slc4a10. In the neocortex paired pulse depression was increased. Though short term plasticity is modulated via Slc4a10, long term potentiation appears independent of Slc4a10. Our data support that Slc4a10 dampens neuronal excitability and thus sheds light on the pathophysiology of SLC4A10 associated pathologies.

Short-term plasticity regulates the excitation/inhibition ratio and the temporal window for spike integration in CA1 pyramidal cells.

Many neurodevelopmental and neuropsychiatric disorders involve an imbalance between excitation and inhibition caused by synaptic alterations. The proper excitation/inhibition (E/I) balance is especially critical in CA1 pyramidal cells, because they control hippocampal output. Activation of Schaffer collateral axons causes direct excitation of CA1 pyramidal cells, quickly followed by disynaptic feedforward inhibition, stemming from synaptically induced firing of GABAergic interneurons. Both excitatory and inhibitory synapses are modulated by short-term plasticity, potentially causing dynamic tuning of the E/I ratio. However, the effects of short-term plasticity on the E/I ratio in CA1 pyramidal cells are not yet known. To determine this, we recorded disynaptic inhibitory postsynaptic currents and the E/I ratio in CA1 pyramidal cells in acute hippocampal slices from juvenile mice. We found that, whereas inhibitory synapses had paired-pulse depression, disynaptic inhibition instead had paired-pulse facilitation (≤200-ms intervals), caused by increased recruitment of feedforward interneurons. Although enhanced disynaptic inhibition helped to constrain paired-pulse facilitation of excitation, the E/I ratio was still larger on the second pulse, increasing pyramidal cell spiking. Surprisingly, this occurred without compromising the precision of spike timing. The E/I balance regulates the temporal spike integration window from multiple inputs; here, we showed that paired-pulse stimulation can broaden the spike integration window. Together, our findings show that the combined effects of short-term plasticity of disynaptic inhibition and monosynaptic excitation alter the E/I balance in CA1 pyramidal cells, leading to dynamic modulation of spike probability and the spike integration window. Short-term plasticity is therefore an important mechanism for modulating signal processing of hippocampal output.

Speech training alters consonant and vowel responses in multiple auditory cortex fields

Speech sounds evoke unique neural activity patterns in primary auditory cortex (A1). Extensive speech sound discrimination training alters A1 responses. While the neighboring auditory cortical fields each contain information about speech sound identity, each field processes speech sounds differently. We hypothesized that while all fields would exhibit training-induced plasticity following speech training, there would be unique differences in how each field changes. In this study, rats were trained to discriminate speech sounds by consonant or vowel in quiet and in varying levels of background speech-shaped noise. Local field potential and multiunit responses were recorded from four auditory cortex fields in rats that had received 10 weeks of speech discrimination training. Our results reveal that training alters speech evoked responses in each of the auditory fields tested. The neural response to consonants was significantly stronger in anterior auditory field (AAF) and A1 following speech training. The neural response to vowels following speech training was significantly weaker in ventral auditory field (VAF) and posterior auditory field (PAF). This differential plasticity of consonant and vowel sound responses may result from the greater paired pulse depression, expanded low frequency tuning, reduced frequency selectivity, and lower tone thresholds, which occurred across the four auditory fields. These findings suggest that alterations in the distributed processing of behaviorally relevant sounds may contribute to robust speech discrimination.

Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus

Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5-12 Hz) and gamma (20-80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 μM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability (pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.

Properties of the primary somatosensory cortex projection to the primary motor cortex in the mouse.

The primary somatosensory (S1) and primary motor (M1) cortices are reciprocally connected, and their interaction has long been hypothesized to contribute to coordinated motor output. Very little is known, however, about the nature and synaptic properties of the S1 input to M1. Here we wanted to take advantage of a previously developed sensorimotor slice preparation that preserves much of the S1-to-M1 connectivity (Rocco MM, Brumberg JC. J Neurosci Methods 162: 139-147, 2007), as well as available optogenetic methodologies, in order to investigate the synaptic profile of this projection. Our data show that S1 input to pyramidal cells of M1 is highly homogeneous, possesses many features of a "driver" pathway, such as paired-pulse depression and lack of metabotropic glutamate receptor activation, and is mediated through axons that terminate in both small and large synaptic boutons. Our data suggest that S1 provides M1 with afferents that possess synaptic and anatomical characteristics ideal for the delivery of strong inputs that can "drive" postsynaptic M1 cells, thereby potentially affecting their output.

Different pharmacology of N-desmethylclozapine at human and rat M2 and M 4 mAChRs in neocortex.

Cholinergic transmission plays a pivotal role in learning, memory and cognition, and disturbances of cholinergic transmission have been implicated in neurological disorders including Alzheimer's disease, epilepsy and schizophrenia. Pharmacological alleviation of these diseases by drugs including N-desmethylclozapine (NDMC), promising in animal models, often fails in patients. We therefore compared the effects of NDMC on glutamatergic and GABAergic transmission in slices from rat and human neocortex. We used carbachol (CCh; an established agonist at metabotropic muscarinic acetylcholine (ACh) receptors (mAChRs)) as a reference. Standard electrophysiological methods including intracellular and field potential recordings were used. In the rat neocortex, NDMC prevented the CCh-induced decrease of GABAA and GABAB receptor-mediated responses but not the CCh-induced increase of the paired-pulse depression. NDMC reduced neither the amplitude of the excitatory postsynaptic potentials (EPSP) nor antagonized the CCh-induced depression of EPSP. In the human neocortex, however, NDMC failed to prevent CCh-induced decrease of the GABAB responses and directly reduced the amplitude of EPSP. These data suggest distinct effects of NDMC in rat and human at M2 and M4 mAChRs underlying presynaptic modulation of GABA and glutamate release, respectively. In particular, NDMC might be a M2 mAChR antagonist in the rat but has no activity at this receptor in human neocortex. However, NDMC has an agonistic effect at M4 mAChR in the human but no such effect in the rat neocortex. The present study confirms that pharmacology at mAChRs can differ between species and emphasizes the need of studies in human tissue.

Visual experience prevents dysregulation of GABAB receptor-dependent short-term depression in adult superior colliculus.

Progressive loss of plasticity during development prevents refined circuits from regressing to an immature state and is thought to depend on maturation of GABAergic inhibition. For example, a gradual reduction in size of visual receptive fields (RFs) occurs in the superior colliculus (SC) during development. Maintenance of the refined state throughout adulthood requires early light exposure. Here we investigate the potential role of changes in long- or short-term plasticity in experience-dependent maintenance of refined RFs. Using an acute SC slice preparation, we found that long-term plasticity was not affected by visual deprivation, indicating that it does not underlie deprivation-induced RF enlargement. In contrast, visual deprivation altered short-term plasticity in an unexpected way. Specifically, GABAB receptor (GABABR)-mediated paired pulse depression was increased in slices from dark-reared animals. This increase was mimicked by GABAAR blockade in slices from normally reared animals, suggesting that experience-dependent maintenance of GABAAR function prevents an increase in probability of neurotransmitter release. GABABR-mediated short-term depression in response to strong stimulation (such as occurs during vision) was reduced in slices from dark-reared animals. This change was mimicked in slices from normal animals by reducing GABA release. These results are consistent with the hypothesis that early visual experience maintains GABAergic inhibition and prevents later deprivation-induced alterations of short-term depression in SC. Identifying how plasticity is restricted in mature circuits could guide therapies to enhance recovery of function in adults.

Co-expression of VGLUT1 and VGAT sustains glutamate and GABA co-release and is regulated by activity in cortical neurons.

In adult neocortex, VGLUT1 (also known as SLC17A7), the main glutamate vesicular transporter, and VGAT (also known as SLC32A1), the γ-aminobutyric acid (GABA) vesicular transporter, are co-expressed in a subset of axon terminals forming both symmetric and asymmetric synapses, where they are sorted into the same vesicles. However, the functional consequence of this colocalization in cortical neurons has not been clarified. Here, we tested the hypothesis that cortical axon terminals co-expressing VGLUT1 and VGAT can evoke simultaneously monosynaptic glutamate and GABA responses, and investigated whether the amount of terminals co-expressing VGLUT1 and VGAT is affected by perturbations of excitation-inhibition balance. In rat primary cortical neurons, we found that a proportion of synaptic and autaptic responses were indeed sensitive to consecutive application of selective glutamate and GABAA receptor blockers. These 'mixed' synapses exhibited paired-pulse depression. Notably, reducing the activity of the neuronal network by treatment with glutamate receptor antagonists decreased the amount of 'mixed' synapses, whereas reducing spontaneous inhibition by treatment with bicuculline increased them. These synapses might contribute to homeostatic regulation of excitation-inhibition balance.

Synaptic vesicle glycoprotein 2A modulates vesicular release and calcium channel function at peripheral sympathetic synapses.

Synaptic vesicle glycoprotein (SV)2A is a transmembrane protein found in secretory vesicles and is critical for Ca(2+) -dependent exocytosis in central neurons, although its mechanism of action remains uncertain. Previous studies have proposed, variously, a role of SV2 in the maintenance and formation of the readily releasable pool (RRP) or in the regulation of Ca(2+) responsiveness of primed vesicles. Such previous studies have typically used genetic approaches to ablate SV2 levels; here, we used a strategy involving small interference RNA (siRNA) injection to knockdown solely presynaptic SV2A levels in rat superior cervical ganglion (SCG) neuron synapses. Moreover, we investigated the effects of SV2A knockdown on voltage-dependent Ca(2+) channel (VDCC) function in SCG neurons. Thus, we extended the studies of SV2A mechanisms by investigating the effects on vesicular transmitter release and VDCC function in peripheral sympathetic neurons. We first demonstrated an siRNA-mediated SV2A knockdown. We showed that this SV2A knockdown markedly affected presynaptic function, causing an attenuated RRP size, increased paired-pulse depression and delayed RRP recovery after stimulus-dependent depletion. We further demonstrated that the SV2A-siRNA-mediated effects on vesicular release were accompanied by a reduction in VDCC current density in isolated SCG neurons. Together, our data showed that SV2A is required for correct transmitter release at sympathetic neurons. Mechanistically, we demonstrated that presynaptic SV2A: (i) acted to direct normal synaptic transmission by maintaining RRP size, (ii) had a facilitatory role in recovery from synaptic depression, and that (iii) SV2A deficits were associated with aberrant Ca(2+) current density, which may contribute to the secretory phenotype in sympathetic peripheral neurons.

Presynaptic Ca2+-permeable AMPA-receptors modulate paired-pulse depression in nociceptive sensory synapses

The role of Ca2+-permeable AMPA-receptors (CP-AMPARs) in the induction of paired-pulse depression (PPD) at glutamatergic nociceptive sensory synapses was examined in co-culture of rat’s dorsal root ganglion and dorsal horn neurons. CP-AMPARs make a considerable contribution to excitatory postsynaptic currents recorded in DH neurons following action potential generation in nociceptive DRG neurons. Activation of CP-AMPARs during fast synaptic transmission induces strong PPD (with a 200ms inter-pulse interval). Blockage of CP-AMPARs with Naspm (100μM) results in most cases in a significant reduction of the PPD magnitude, also reversing to paired-pulse facilitation in some cases. However, loading of postsynaptic DH neurons with BAPTA (10mM) did not alter the effect of Naspm (100μM) on the paired-pulse ratio. Our data provide evidence that presynaptic CP-AMPARs in nociceptive sensory synapses regulate the magnitude of PPD and that postsynaptic Ca2+-permeable glutamatergic receptors are not required for PPD induction.

Decrease of neocortical paired-pulse depression in GAERS and possible implication of gap junctions

Thalamocortical slices are widely used to study thalamocortical relationships and absence epilepsy. However, it is still not known whether (1) intracortical synaptic transmission, in particular neocortical paired-pulse depression (PPD), is maintained in these slices and (2) whether PPD is altered in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS, a model of absence epilepsy for which cortico-thalamic loops are involved). Furthermore, while the involvement of gap junctions (GJ) in the mechanisms leading to epileptiform discharges has been intensively studied, little is known about their effect on intracortical transmission. We first studied intracortical connection efficacy and PPD in thalamocortical slices from GAERS and non-epileptic rats (NER). We then investigated the effects of GJ blockers (carbenoxolone and quinidine) on intracortical response following single or paired-pulse stimulations in coronal slices from Wistar rats. We show that the efficacy of intracortical connections is not impaired in GAERS. We also show that neocortical PPD is preserved in thalamocortical slices of NER, but that its efficacy is strongly decreased in GAERS. Moreover, a NMDA antagonist strongly reduced the PPD in NER but had no effect in GAERS. Cortical responses to white matter stimulation were not modified by quinidine or carbenoxolone in coronal slices of Wistar rats. PPD was recorded in these slices and was decreased by carbenoxolone but not by quinidine. We hypothesize that the decrease of PPD observed in GAERS might be due to a decrease in function of (1) NMDA receptors and/or (2) astrocytic GJ’s.

A model of order-selectivity based on dynamic changes in the balance of excitation and inhibition produced by short-term synaptic plasticity

Determining the order of sensory events separated by a few hundred milliseconds is critical to many forms of sensory processing, including vocalization and speech discrimination. Although many experimental studies have recorded from auditory order-sensitive and order-selective neurons, the underlying mechanisms are poorly understood. Here we demonstrate that universal properties of cortical synapses-short-term synaptic plasticity of excitatory and inhibitory synapses-are well suited for the generation of order-selective neural responses. Using computational models of canonical disynaptic circuits, we show that the dynamic changes in the balance of excitation and inhibition imposed by short-term plasticity lead to the generation of order-selective responses. Parametric analyses predict that among the forms of short-term plasticity expressed at excitatory-to-excitatory, excitatory-to-inhibitory, and inhibitory-to-excitatory synapses, the single most important contributor to order-selectivity is the paired-pulse depression of inhibitory postsynaptic potentials (IPSPs). A topographic model of the auditory cortex that incorporates short-term plasticity accounts for both context-dependent suppression and enhancement in response to paired tones. Together these results provide a framework to account for an important computational problem based on ubiquitous synaptic properties that did not yet have a clearly established computational function. Additionally, these studies suggest that disynaptic circuits represent a fundamental computational unit that is capable of processing both spatial and temporal information.

Altered synaptic transmission at olfactory and vomeronasal nerve terminals in mice lacking N-type calcium channel Cav2.2.

We investigated the role of voltage-activated calcium (Cav) channels for synaptic transmission at mouse olfactory and vomeronasal nerve terminals at the first synapse of the main and accessory olfactory pathways, respectively. We provided evidence for a central role of the N-type Cav channel subunit Cav2.2 in presynaptic transmitter release at these synapses. Striking Cav2.2 immunoreactivity was localised to the glomerular neuropil of the main olfactory bulb (MOB) and accessory olfactory bulb (AOB), and co-localised with presynaptic molecules such as bassoon. Voltage-clamp recordings of sensory nerve-evoked, excitatory postsynaptic currents (EPSCs) in mitral/tufted (M/T) and superficial tufted cells of the MOB and mitral cells of the AOB, in combination with established subtype-specific Cav channel toxins, indicated a predominant role of N-type channels in transmitter release at these synapses, whereas L-type, P/Q-type, and R-type channels had either no or only relatively minor contributions. In Cacna1b mutant mice lacking the Cav2.2 (α1B) subunit of N-type channels, olfactory nerve-evoked M/T cell EPSCs were not reduced but became blocker-resistant, thus indicating a major reorganisation and compensation of Cav channel subunits as a result of the Cav2.2 deletion at this synapse. Cav2.2-deficient mice also revealed that Cav2.2 was critically required for paired-pulse depression of olfactory nerve-evoked EPSCs in M/T cells of the MOB, and they demonstrated an essential requirement for Cav2.2 in vomeronasal nerve-evoked EPSCs of AOB mitral cells. Thus, Cacna1b loss-of-function mutations are unlikely to cause general anosmia but Cacna1b emerges as a strong candidate in the search for mutations causing altered olfactory perception, such as changes in general olfactory sensitivity and altered social responses to chemostimuli.

YAC128 Huntington׳s disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease

Huntington׳s disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder.

Regulating hippocampal hyperexcitability through GABAB Receptors.

Abstract Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability.

Regulating hippocampal hyperexcitability through GABAB Receptors

Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein‐coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure‐related hyperexcitability.

Increased Hippocampal Excitability in the 3xTgAD Mouse Model for Alzheimer's Disease In Vivo

Mouse Alzheimer's disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be due to the development of an abnormal hyper-excitable state in the hippocampal formation.

Glutamate and Dopamine Transmission from Midbrain Dopamine Neurons Share Similar Release Properties But Are Differentially Affected by Cocaine

Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals.

Intrinsic properties of and thalamocortical inputs onto identified corticothalamic-VPM neurons

Corticothalamic (CT) feedback plays an important role in regulating the sensory information that the cortex receives. Within the somatosensory cortex layer VI originates the feedback to the ventral posterior medial (VPM) nucleus of the thalamus, which in turn receives sensory information from the contralateral whiskers. We examined the physiology and morphology of CT neurons in rat somatosensory cortex, focusing on the physiological characteristics of the monosynaptic inputs that they receive from the thalamus. To identify CT neurons, rhodamine microspheres were injected into VPM and allowed to retrogradely transport to the soma of CT neurons. Thalamocortical slices were prepared at least 3 days post injection. Whole-cell recordings from labeled CT cells in layer VI demonstrated that they are regular spiking neurons and exhibit little spike frequency adaption. Two anatomical classes were identified based on their apical dendrites that either terminated by layer V (compact cells) or layer IV (elaborate cells). Thalamic inputs onto identified CT-VPM neurons demonstrated paired pulse depression over a wide frequency range (2–20 Hz). Stimulus trains also resulted in significant synaptic depression above 10 Hz. Our results suggest that thalamic inputs differentially impact CT-VPM neurons in layer VI. This characteristic may allow them to differentiate a wide range of stimulation frequencies which in turn further tune the feedback signals to the thalamus.

Neuronal mechanisms of epileptogenesis

Neuronal mechanisms of epileptogenesis