Background activity and visual responsiveness of caudate nucleus neurons in halothane anesthetized and in awake, behaving cats.

This study focuses on the important question whether brain activity recorded from anesthetized, paralyzed animals is comparable to that recorded from awake, behaving ones. We compared neuronal activity recorded from the caudate nucleus (CN) of two halothane-anesthetized, paralyzed and two awake, behaving cats. In both models, extracellular recordings were made from the CN during static and dynamic visual stimulation. The anesthesia was maintained during the recordings by a gaseous mixture of air and halothane (1.0%). The behaving animals were trained to perform a visual fixation task. Based on their electrophysiological properties, the recorded CN neurons were separated into three different classes: phasically active (PANs), high firing (HFNs), and tonically active (TANs) neurons. Halothane anesthesia significantly decreased the background activity of the CN neurons in all three classes. The anesthesia had the most remarkable suppressive effect on PANs, where the background activity was consistently under 1 spike/s. The analysis of these responses was almost impossible due to the extremely low activity. The evoked responses during both static and dynamic visual stimulation were obvious in the behaving cats. On the other hand, only weak visual responses were found in some neurons of halothane anesthetized cats. These results show that halothane gas anesthesia has a marked suppressive effect on the feline CN. We suggest that for the purposes of the visual and related multisensory/sensorimotor electrophysiological exploration of the CN, behaving animal models are preferable over anesthetized ones.

Activity of Caudate Nucleus Neurons in a Visual Fixation Paradigm in Behaving Cats.

Beside its motor functions, the caudate nucleus (CN), the main input structure of the basal ganglia, is also sensitive to various sensory modalities. The goal of the present study was to investigate the effects of visual stimulation on the CN by using a behaving, head-restrained, eye movement-controlled feline model developed recently for this purpose. Extracellular multielectrode recordings were made from the CN of two cats in a visual fixation paradigm applying static and dynamic stimuli. The recorded neurons were classified in three groups according to their electrophysiological properties: phasically active (PAN), tonically active (TAN) and high-firing (HFN) neurons. The response characteristics were investigated according to this classification. The PAN and TAN neurons were sensitive primarily to static stimuli, while the HFN neurons responded primarily to changes in the visual environment i.e. to optic flow and the offset of the stimuli. The HFNs were the most sensitive to visual stimulation; their responses were stronger than those of the PANs and TANs. The majority of the recorded units were insensitive to the direction of the optic flow, regardless of group, but a small number of direction-sensitive neurons were also found. Our results demonstrate that both the static and the dynamic components of the visual information are represented in the CN. Furthermore, these results provide the first piece of evidence on optic flow processing in the CN, which, in more general terms, indicates the possible role of this structure in dynamic visual information processing.

Anxious and nonanxious mice show similar hippocampal sensory evoked oscillations under urethane anesthesia: difference in the effect of buspirone.

Hippocampal oscillations recorded under urethane anesthesia are proposed to be modulated by anxiolytics. All classes of clinically effective anxiolytics were reported to decrease the frequency of urethane theta; however, recent findings raise concerns about the direct correlation of anxiolysis and the frequency of hippocampal theta. Here, we took advantage of our two inbred mouse strains displaying extremes of anxiety (anxious (AX) and nonanxious (nAX)) to compare the properties of hippocampal activity and to test the effect of an anxiolytic drugs. No difference was observed in the peak frequency or in the peak power between AX and nAX strains. Buspirone (Bus) applied in 2.5 mg/kg decreased anxiety of AX but did not have any effect on nAX as was tested by elevated plus maze and open field. Interestingly, Bus treatment increased hippocampal oscillatory frequency in the AX but left it unaltered in nAX mice. Saline injection did not have any effect on the oscillation. Paired-pulse facilitation was enhanced by Bus in the nAX, but not in the AX strain. Collectively, these results do not support the hypothesis that hippocampal activity under urethane may serve as a marker for potential anxiolytic drugs. Moreover, we could not confirm the decrease of frequency after anxiolytic treatment.

GluA1 phosphorylation alters evoked firing pattern in vivo.

AMPA and NMDA receptors convey fast synaptic transmission in the CNS. Their relative contribution to synaptic output and phosphorylation state regulate synaptic plasticity. The AMPA receptor subunit GluA1 is central in synaptic plasticity. Phosphorylation of GluA1 regulates channel properties and trafficking. The firing rate averaged over several hundred ms is used to monitor cellular input. However, plasticity requires the timing of spiking within a few ms; therefore, it is important to understand how phosphorylation governs these events. Here, we investigate whether the GluA1 phosphorylation (p-GluA1) alters the spiking patterns of CA1 cells in vivo. The antidepressant Tianeptine was used for inducing p-GluA1, which resulted in enhanced AMPA-evoked spiking. By comparing the spiking patterns of AMPA-evoked activity with matched firing rates, we show that the spike-trains after Tianeptine application show characteristic features, distinguishing from spike-trains triggered by strong AMPA stimulation. The interspike-interval distributions are different between the two groups, suggesting that neuronal output may differ when new inputs are activated compared to increasing the gain of previously activated receptors. Furthermore, we also show that NMDA evokes spiking with different patterns to AMPA spike-trains. These results support the role of the modulation of NMDAR/AMPAR ratio and p-GluA1 in plasticity and temporal coding.

Tianeptine potentiates AMPA receptors by activating CaMKII and PKA via the p38, p42/44 MAPK and JNK pathways.

Impairments of cellular plasticity appear to underlie the pathophysiology of major depression. Recently, elevated levels of phosphorylated AMPA receptor were implicated in the antidepressant effect of various drugs. Here, we investigated the effects of an antidepressant, Tianeptine, on synaptic function and GluA1 phosphorylation using murine hippocampal slices and in vivo single-unit recordings. Tianeptine, but not imipramine, increased AMPA receptor-mediated neuronal responses both in vitro and in vivo, in a staurosporine-sensitive manner. Paired-pulse ratio was unaltered by Tianeptine, suggesting a postsynaptic site of action. Tianeptine, 10 µM, enhanced the GluA1-dependent initial phase of LTP, whereas 100 µM impaired the latter phases, indicating a critical role of GluA1 subunit phosphorylation in the excitation. Tianeptine rapidly increased the phosphorylation level of Ser(831)-GluA1 and Ser(845)-GluA1. Using H-89 and KN-93, we show that the activation of both PKA and CaMKII is critical in the effect of Tianeptine on AMPA responses. Moreover, the phosphorylation states of Ser(217/221)-MEK and Thr(183)/Tyr(185)-p42MAPK were increased by Tianeptine and specific kinase blockers of the MAPK pathways (PD 98095, SB 203580 and SP600125) prevented the effects of Tianeptine. Overall these data suggest that Tianeptine potentiates several signaling cascades associated with synaptic plasticity and provide further evidence that a major mechanism of action for Tianeptine is to act as an enhancer of glutamate neurotransmission via AMPA receptors.

Fibrillar Abeta (1-42) enhances NMDA receptor sensitivity via the integrin signaling pathway.

The aggregated form of amyloid-beta (Abeta) (1-42) has been shown to increase N-methyl-D-aspartic acid (NMDA) evoked neuronal activity in vivo. Here we further characterized this phenomenon by investigating the role of integrin activation and downstream Src kinase activity using in vivo electrophysiology and in vitro intracellular Ca (2+) measurements. Pretreatment of differentiated SH-SY5Y cells with fibrillar Abeta (1-42) markedly enhanced the intracellular calcium increases caused by NMDA receptor (NMDA-R) stimulation. Function blocking antibody against beta1 integrin depressed the facilitatory effects of Abeta (1-42). Similarly, Abeta (1-42) facilitated NMDA-R driven firing of hippocampal neurons in vivo, and this effect was reduced by neutralizing antibody against beta1 integrins. The positive action of Abeta (1-42) on NMDA-R dependent responses was also depressed by an inhibitor known to block Src kinase. These results support the hypothesis that aggregated Abeta (1-42) is recognized by the beta1 subunit containing integrins and may induce a Src kinase dependent NMDA receptor phosphorylation.