Injection Of Muscimol Research Articles

Sleep and Anesthesia

Sleep and Anesthesia

AT1 receptor blockade in the lateral parabrachial nucleus reduces the effects of muscimol on sodium intake

The blockade of the lateral parabrachial nucleus (LPBN) with GABAA receptor agonist muscimol induces robust hypertonic NaCl and water intake by rats. In the present study we investigated the effects of previous injections of losartan (AT1 angiotensin receptor antagonist) into the LPBN on 0.3M NaCl and water intake induced by muscimol injected bilaterally in the same area in fluid replete rats and in rats treated with the diuretic furosemide combined with a low dose of the angiotensin-converting enzyme inhibitor captopril injected subcutaneously. Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. Bilateral injections of muscimol (0.5nmol/0.2μl, n=8) into the LPBN in fluid replete rats induced 0.3M NaCl intake (23.4±4.1 vs. saline: 0.4±0.4ml/3h) and water intake (9.3±1.9 vs. saline: 0.7±0.4ml/3h) and pre-treatment of the LPBN with losartan (50μg/0.2μl) reduced 0.3M NaCl intake (3.3±2.5ml/3h) and water intake (4.0±2.9ml/3h) induced by muscimol. In rats treated with furosemide+captopril, pre-treatment with losartan into the LPBN attenuated the increase of 0.3M NaCl intake produced by muscimol (12.8±5.3, vs. saline+muscimol: 36.7±6.7ml/3h) without changing water intake. Therefore, the results suggest that deactivation of LPBN inhibitory mechanisms by muscimol injections into the LPBN is facilitated by endogenous angiotensin II acting on AT1 receptors in the LPBN, which drives rats to ingest large amounts of hypertonic NaCl.

Contribution of the retino‐tectal pathway to visually guided saccades after lesion of the primary visual cortex in monkeys

Previous reports on 'blindsight' have shown that some patients with lesions of the primary visual cortex (V1) could localize visual targets in their scotoma with hand and/or eye movements without visual awareness. A role of the retino-tectal pathway on residual vision has been proposed but the direct evidence for this still remains sparse. To examine this possibility, we inactivated the superior colliculus (SC) of unilateral V1-lesioned monkeys using microinjections of muscimol, and analysed the effects on visually guided saccades. Following muscimol injections into the contralesional SC, the monkeys performed the visually guided saccade task with relatively minor deficits. The effects of ipsilesional SC inactivation were more severe. After injections, the monkeys failed to localize the target within the visual field represented at the injection site on the SC map. The effects of ipsilesional SC inactivation may result from sensory deficits, motor deficits or a combination of both. To examine these possibilities, we tested the effects of SC inactivation on the motor system by investigating spontaneous saccades. After inactivation of the ipsilesional SC, spontaneous saccades toward the injection site were not abolished, suggesting that impairment of visually guided saccades following inactivation of the ipsilesional SC could not be explained solely by a motor deficit and was primarily due to a visual deficit, presumably by interfering with processing in the superficial layer. We conclude that the retino-tectal pathway plays an essential role in residual vision after V1 lesion. The results suggest that this pathway may be involved in mediating unconscious vision in blindsight patients.

Superior Colliculus Inactivation Alters the Weighted Integration of Visual Stimuli

The primate superior colliculus (SC) is important for the winner-take-all selection of targets for orienting movements. Such selection takes time, however, and the earliest motor responses typically are guided by a weighted vector average of the visual stimuli, before the winner-take-all selection of a single target. We tested whether SC activity plays a role in this initial stage of orienting by inactivating the SC in two macaques (Macaca mulatta) with local muscimol injections. After SC inactivation, initial orienting responses still followed a vector average, but the contribution of the visual stimulus inside the affected field was decreased, and the contribution of the stimulus outside the affected field was increased. These results demonstrate that the SC plays an important role in the weighted integration of visual signals for orienting, in addition to its role in the winner-take-all selection of the target.

Effect of inactivation and disinhibition of the oculomotor vermis on saccade adaptation

The ability to adapt a variety of motor acts to compensate for persistent natural or artificially induced errors in movement accuracy requires the cerebellum. For adaptation of the rapid shifts in the direction of gaze called saccades, the oculomotor vermis (OMV) of the cerebellum must be intact. We disrupted the neural circuitry of the OMV by manipulating gamma aminobutyric acid (GABA), the transmitter used by many neurons in the vermis. We injected either muscimol, an agonist of GABA, to inactivate the OMV or bicuculline, an antagonist, to block GABA inhibition. Our previous study showed that muscimol injections cause ipsiversive saccades to fall short of their targets, whereas bicuculline injections cause most ipsiversive saccades to overshoot. Once these dysmetrias had stabilized, we tested the monkey's ability to adapt saccade size to intra-saccadic target steps that produced a consistent saccade under-shoot (amplitude increase adaptation required) or overshoot (amplitude decrease adaptation required). Injections of muscimol abolished the amplitude increase adaptation of ipsiversive saccades, but had either no effect, or occasionally facilitated, amplitude decrease adaptation. In contrast, injections of bicuculline impaired amplitude decrease adaptation and usually facilitated amplitude increase adaptation. Neither drug produced consistent effects on the adaptation of contraversive saccades. Taken together, these data suggest that OMV activity is necessary for amplitude increase adaptation, whereas amplitude decrease adaptation may involve the inhibitory circuits within the OMV.

Inactivation of ventral midline thalamus produces selective spatial delayed conditional discrimination impairment in the rat

The reuniens (Re) and rhomboid (Rh) nuclei are organized to influence activity in distributed limbic networks involving hippocampus and medial prefrontal cortex (mPFC). To elucidate the role of these nuclei in spatial memory we inactivated Re and Rh in rats with the GABA(A) agonist muscimol and compared effects on two spatial delayed conditional discriminations: delayed nonmatching to position (DNMTP) and varying choice radial maze delayed nonmatching (VC-DNM). DNMTP is trained in operant chambers and requires rats to choose between the same two levers on all trials. VC-DNM is trained in automated radial mazes and requires rats to choose between two arms, randomly selected from eight alternatives on each trial. DNMTP is affected by hippocampal and mPFC lesions while VC-DNM is affected by hippocampal, but not mPFC lesions (Porter et al. (2000) Behav Brain Res 109:69-81). We found evidence of a localized (low dose) effect of ReRh inactivation on DNMTP but not VC-DNM. This was confirmed by comparison with muscimol injections in an anatomical control site. These results are consistent with evidence that Re and Rh affect measures of spatial working memory that depend on interactions between hippocampus and mPFC, but not measures that depend on hippocampus alone.

Involvement of dorsal hippocampal muscarinic cholinergic receptors on muscimol state-dependent memory of passive avoidance in mice

Aims In the present study, the effects of bilateral intra-dorsal hippocampal (intra-CA1) injections of cholinergic agents on muscimol state-dependent memory were examined in mice. Main methods A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Key findings Pre-training intra-CA1 administration of a GABA-A receptor agonist, muscimol (0.05 and 0.1 μg/mouse) dose dependently induced impairment of memory retention. Pre-test injection of muscimol (0.05 and 0.1 μg/mouse, intra-CA1) induced state-dependent retrieval of the memory acquired under pre-training muscimol (0.1 μg/mouse, intra-CA1) influence. Pre-test intra-CA1 injection of an acetylcholinesterase inhibitor, physostigmine (0.5 and 1 μg/mouse, intra-CA1) reversed the memory impairment induced by pre-training administration of muscimol (0.1 μg/mouse, intra-CA1). Moreover, pre-test administration of physostigmine (0.5 and 1 μg/mouse, intra-CA1) with an ineffective dose of muscimol (0.025 μg/mouse, intra-CA1) significantly restored the retrieval and induced muscimol state-dependent memory. Pre-test intra-CA1 administration of physostigmine (0.25, 0.5 and 1 μg/mouse) by itself cannot affect memory retention. Pre-test intra-CA1 injection of the muscarinic receptor antagonist, atropine (1 and 2 μg/mouse) 5 min before the administration of muscimol (0.1 μg/mouse, intra-CA1) dose dependently inhibited muscimol state-dependent memory. Pre-test intra-CA1 administration of atropine (0.5, 1 and 2 μg/mouse) by itself cannot affect memory retention. Significance The results suggest that muscarinic cholinergic mechanism of the CA1 may influence muscimol state-dependent memory.

A Neural Correlate of the Processing of Multi-Second Time Intervals in Primate Prefrontal Cortex

Several areas of the brain are known to participate in temporal processing. Neurons in the prefrontal cortex (PFC) are thought to contribute to perception of time intervals. However, it remains unclear whether the PFC itself can generate time intervals independently of external stimuli. Here we describe a group of PFC neurons in area 9 that became active when monkeys recognized a particular elapsed time within the range of 1–7 seconds. Another group of area 9 neurons became active only when subjects reproduced a specific interval without external cues. Both types of neurons were individually tuned to recognize or reproduce particular intervals. Moreover, the injection of muscimol, a GABA agonist, into this area bilaterally resulted in an increase in the error rate during time interval reproduction. These results suggest that area 9 may process multi-second intervals not only in perceptual recognition, but also in internal generation of time intervals.

Hypherphagia caused by muscimol injection in the nucleus raphe dorsalis of rats: its control by 5-hydroxytryptamine in the nucleus accumbens

Muscimol injection in the nucleus raphe dorsalis caused intense eating by rats with access to food. A dose-related reduction of muscimol's effect was found after bilateral injections of 5-hydroxytryptamine (5-HT) in the nucleus accumbens (dose range 2.2-8.8 micrograms in 2 microliter) but no effect was observed when an even higher dose (17.6 micrograms) of 5-HT was injected in the caudate putamen. Eating by food-deprived rats was not changed by any dose of 5-HT injected either into the nucleus accumbens or the caudate putamen. (+)-Norfenfluramine, 20 micrograms, injected in the nucleus accumbens also reduced muscimol-induced eating but had no effect on the food intake of starved rats. The results suggest an important role of 5-HT in the nucleus accumbens in the control of certain types of hyperphagia in rats.

Role of the A5 noradrenergic neurons in the control of central chemoreflex in rats

Central chemoreflex stimulation produces an increase in breathing and sympathetic discharge. The A5 noradrenergic region project to several brainstem areas involved in autonomic regulation and contributes to the increase in sympathetic discharge elicited by peripheral chemoreflex activation. Here we ask whether the A5 noradrenergic region could contribute to central chemoreflex activation. In urethane anaesthetized sino-aortic denervated and vagotomized male Wistar rats (n = 8/group), hypercapnia (end-expiratory CO2 from 5% to 10%) increased MAP (Δ = +33 ± 4 mmHg), sSNA (Δ = +97 ± 13%), PNA frequency (Δ = +57 ± 11%) and amplitude (Δ = +42 ± 9%). Bilateral injection of muscimol (GABA-A agonist - 100 pmol/50 nl) into the A5 region reduced the rise in MAP (Δ = +19 ± 3 mmHg), sSNA (Δ = +63 ± 5%) and PNA frequency and amplitude (Δ = +38 ± 4% and Δ = +30 ± 6%, respectively) produced by hypercapnia. Bilateral inhibition of A5 region with the immunotoxin anti-dopamine β-hydroxylase-saporin (anti-DβH-SAP) reduced the increase in MAP (Δ = +22 ± 3 mmHg), sSNA (Δ = +68 ± 9%) and PNA amplitude (Δ = +33 ± 7%, respectively). The results suggest that A5 noradrenergic neurons contribute to the increase in MAP, sSNA and PNA activation during central chemoreflex stimulation. Financial support: FAPESP (06/60174-9 to TSM, 09/13333-9 to CLT).

Inactivation of the putamen selectively impairs reward history-based action selection

Behavioral decisions and actions are directed to achieve specific goals and to obtain rewards and escape punishments. Previous studies involving the recording of neuronal activity suggest the involvement of the cerebral cortex, basal ganglia, and midbrain dopamine system in these processes. The value signal of the action options is represented in the striatum, updated by reward prediction errors, and used for selecting higher-value actions. However, it remains unclear whether dysfunction of the striatum leads to impairment of value-based action selection. The present study examined the effect of inactivation of the putamen via local injection of the GABAA receptor agonist muscimol in monkeys engaged in a manual reward-based multi-step choice task. The monkeys first searched a reward target from three alternatives, based on the previous one or two choices and their outcomes, and obtained a large reward; they then earned an additional reward by choosing the last rewarded target. Inactivation of the putamen impaired the ability of monkeys to make optimal choices during third trial in which they were required to choose a target different from those selected in the two previous trials by updating the values of the three options. The monkeys normally changed options if the last choice resulted in small reward (lose-shift) and stayed with the last choice if it resulted in large reward (win-stay). Task start time and movement time during individual trials became longer after putamen inactivation. But monkeys could control the motivation level depending on the reward value of individual trial types before and after putamen inactivation. These results support a view that the putamen is involved selectively and critically in neuronal circuits for reward history-based action selection.

Sympathetic Response to Insulin Is Mediated by Melanocortin 3/4 Receptors in the Hypothalamic Paraventricular Nucleus

Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus (PVN) regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether PVN neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose-anesthetized, male Sprague-Dawley rats (280-420 g) by an infusion of insulin (3.75 mU/kg per min) and 50% dextrose (0.75-2.0 mL/h) for 120 minutes. At 90 minutes, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the PVN with bilateral injection of the GABA(A) receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the PVN did not alter lumbar sympathetic nerve activity, and thereby suggests that insulin activates neurons upstream of the PVN. Interestingly, the sympathetic response to insulin was eliminated by PVN injection of the melanocortin 3/4 receptor antagonist SHU9119, but was unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of PVN neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate that insulin activates a melanocortin-dependent pathway to the PVN that increases glutamatergic drive to the rostral ventrolateral medulla and alters cardiovascular function.

Inhibition of the caudal pressor area reduces cardiorespiratory chemoreflex responses

The caudal pressor area (CPA) is a brainstem area located close to the spinal cord. The activation of the CPA increases sympathetic activity and mean arterial pressure (MAP) by mechanisms dependent on the commissural nucleus of the solitary tract (commNTS) and rostroventrolateral medulla, however, the signals that activate the CPA to produce these responses are still unknown. Therefore, in the present study, we investigated the activity of glutamatergic and GABAergic mechanisms from the CPA and commNTS in rats exposed to hypoxia and the effects of the inhibition of CPA neurons on cardiorespiratory responses to peripheral chemoreceptor activation with i.v. sodium cyanide (NaCN). Male Sprague–Dawley rats (250–280 g, n=5–8/group) were used. In conscious rats, most of the commNTS neurons (66±11%) and part of the CPA neurons (36±7%) activated by hypoxia (8% O2) were glutamatergic (contained VGLUT2mRNA). Small part of the neurons activated during hypoxia was GABAergic (contained GAD-67mRNA) in the commNTS (9±4%) or the CPA (6±2%). In urethane anesthetized rats, the inhibition of CPA neurons with bilateral injections of muscimol (GABA-A agonist, 2 mM) reduced baseline MAP, splanchnic sympathetic nerve discharge (SND) and phrenic nerve discharge (PND). Muscimol into the CPA also reduced by around 50% the pressor and sympathoexcitatory responses and the increase in PND to peripheral chemoreceptor activation with NaCN (50 μg/kg i.v.), without changing sympathetic baroreflex responses. These data suggest that CPA mechanisms facilitate cardiorespiratory responses to peripheral chemoreflex activation. Immunohistochemistry results also suggest that at least part of the CPA mechanisms activated by hypoxia is glutamatergic.

Neuronal Activity in the Caudal Frontal Eye Fields of Monkeys during Memory-Based Smooth Pursuit Eye Movements: Comparison with the Supplementary Eye Fields

Recently, we examined the neuronal substrate of predictive pursuit during memory-based smooth pursuit and found that supplementary eye fields (SEFs) contain signals coding assessment and memory of visual motion direction, decision not-to-pursue (“no-go”), and preparation for pursuit. To determine whether these signals were unique to the SEF, we examined the discharge of 185 task-related neurons in the caudal frontal eye fields (FEFs) in 2 macaques. Visual motion memory and no-go signals were also present in the caudal FEF but compared with those in the SEF, the percentage of neurons coding these signals was significantly lower. In particular, unlike SEF neurons, directional visual motion responses of caudal FEF neurons decayed exponentially. In contrast, the percentage of neurons coding directional pursuit eye movements was significantly higher in the caudal FEF than in the SEF. Unlike SEF inactivation, muscimol injection into the caudal FEF did not induce direction errors or no-go errors but decreased eye velocity during pursuit causing an inability to compensate for the response delays during sinusoidal pursuit. These results indicate significant differences between the 2 regions in the signals represented and in the effects of chemical inactivation suggesting that the caudal FEF is primarily involved in generating motor commands for smooth-pursuit eye movements.

Inactivation of the median raphe nucleus increases intake of sucrose solutions: A microstructural analysis.

Previous studies have shown that microinjections of the GABA-A agonist muscimol into the median raphe nucleus (MR) result in large increases in the intake of solid foods. In the current study, we used microstructural techniques to characterize the effects of intra-MR muscimol injections on the consumption of either a 0.05 M or a 0.29 M sucrose solution. After injections of either saline or muscimol, animals consumed more of the 0.29 M than the 0.05 M solution, an effect which resulted primarily from increases in the initial rate of consumption with no change in the rate at which licking decayed across the test session. In contrast, intra-MR muscimol injections had little effect on the initial licking rate, but greatly increased meal duration, indicating that this treatment affected ingestion in a different way than did altering the sucrose concentration. Muscimol injections produced a significantly larger increase in the intake of the 0.29 M than of the 0.05 M solution. Intra-MR muscimol injections did not alter the within burst rate of licking, suggesting that they did not affect the functioning of the licking pattern generator. In contrast, these injections did increase the number of licks contained within "clusters," that is groups of licks separated from each other by intervals of more than 0.5 sec. These findings show that inactivation of the MR produces a powerful effect on the intake of liquid diets, and that the nature of this effect is different from that produced here by changes in sucrose concentration and from those reported after pharmacological manipulations of a number of other brain systems. We additionally discuss several theoretical issues arising in the interpretation of microstructural data. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Role of Striatum in the Pause and Burst Generation in the Globus Pallidus of 6-OHDA-Treated Rats

Electrophysiological studies in patients and animal models of Parkinson's disease (PD) often reported increased burst activity of neurons in the basal ganglia. Neurons in the globus pallidus external (GPe) segment in 6-hydroxydopamine (6-OHDA)-treated hemi-parkinsonian rats fire with strong bursts interrupted by pauses. The goal of this study was to evaluate the hypothesis that dopamine (DA)-depletion increases burst firings of striatal (Str) neurons projecting to the GPe and that the increased Str–GPe burst inputs play a significant role in the generation of pauses and bursts in GPe and its projection sites. To evaluate this hypothesis, the unitary activity of Str and GPe was recorded from control and 6-OHDA-treated rats anesthetized with 0.5–1% isoflurane. The occurrence of pauses and bursts in the firings of GPe neurons was significantly higher in 6-OHDA than in normal rats. Muscimol injection into the Str of 6-OHDA rats increased average firing rate and greatly reduced the pauses and bursts in GPe. Recordings from Str revealed that most of the presumed projection neurons in control rats have very low spontaneous activity, and even the occasional neurons that did exhibit spontaneous burst firings did so with an average rate of less than 2 Hz. In DA-depleted Str, neurons having stronger bursts and a higher average firing rate were encountered more frequently. Juxtacellular labeling revealed that most of these neurons were medium spiny neurons projecting only to GPe. Injection of a behaviorally effective dose of methyl-l-DOPA into the Str of 6-OHDA rats significantly increased the average firing rate and decreased the number of pauses of GPe neurons. These data validate the hypothesis that DA-depletion increases burst firings of Str neurons projecting to the GPe and that the increased Str–GPe burst inputs play a significant role in the generation of pauses and bursts in GPe. These results suggest that treatment to reduce burst Str–GPe inhibitory inputs may help to restore some PD disabilities.

GABAergic mechanisms of anterior and ventromedial hypothalamic nuclei in the expression of freezing in response to a light-conditioned stimulus.

The amygdala, dorsal periaqueductal gray (dPAG), and medial hypothalamus have long been recognized to comprise a neural system responsible for the generation and elaboration of unconditioned fear in the brain. This neural substrate is well known to be under tonic inhibitory control exerted by γ-aminobutyric acid (GABA) mechanisms. Some evidence also suggests that these structures integrate conditioned fear. A recent study using the fear-potentiated startle paradigm showed that GABAergic mechanisms in the anterior hypothalamic nucleus (AHN) and dorsomedial part of the ventromedial hypothalamic nucleus (VMHDM) regulate conditioned fear. The present study examined the extent to which GABAergic mechanisms in these brain regions are involved in conditioned fear by measuring freezing in response to a light used as a conditioned stimulus (CS). The GABAA receptor agonist muscimol and the GABA-synthesizing enzyme glutamic acid decarboxylase inhibitor semicarbazide were used as an enhancer and inhibitor of GABA mechanisms, respectively. Muscimol and semicarbazide were injected into the AHN or VMHDM of rats before fear conditioning. Muscimol injections into the AHN and VMHDM significantly reduced conditioned freezing, whereas inhibition of GABA transmission increased this conditioned response in the AHN. The present study further supports the hypothesis that GABAergic mechanisms in the AHN and VMHDM exert inhibitory control on the neural substrates of conditioned fear in the hypothalamus.

Pharmacology of Intracisternal or Intrathecal Glycine, Muscimol, and Baclofen in Strychnine-induced Thermal Hyperalgesia of Mice

Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABAA receptor agonist), baclofen (a GABAB receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

GABA A Receptors in the Dorsal Hippocampus are Involved in Sate-dependent Learning Induced by Lithium in Mice.

These experiments examined the effects of pre-test intra dorsal hippocampus (intra-CA1) administration of GABAA receptor agonist and antagonist, muscimol and bicuculline respectively, on state-dependent learning induced by lithium. Male NMRI mice were trained in a one-trial step-down inhibitory avoidance task, and immediately after training they received IP injections of either saline (10 mL/kg) or lithium (10 mg/kg). The animals were tested for step-down latency, as an index of inhibitory avoidance memory, 24 h after the training. The results showed that lithium (10 mg/kg) induced state-dependent learning. Although the decrease of step down latency due to post-training lithium (10 mg/kg) was not fully reversed by a lower dose of lithium (5 mg/kg) but pre-test intra-CA1 injection of bicuculline (0.25 μg/mouse) increased the effect of the lower dose of lithium. Pre-test intra-CA1 injection of muscimol (0.05 μg/mouse) by itself reversed the decrease of step-down latency induced by post-training lithium (10 mg/kg). Pre-test intra-CA1 injection of muscimol (0.03 and 0.05 μg/mouse) also disrupted state-dependent learning induced by lithium (10 mg/kg). The results suggest that a GABAA receptor mechanism in the dorsal hippocampus is involved in state-dependent induced by lithium.

Development of asymmetric inhibition underlying direction selectivity in the retina

Establishing precise synaptic connections is crucial to the development of functional neural circuits. The direction-selective circuit in the retina relies upon highly selective wiring of inhibitory inputs from starburst amacrine cells (SACs) onto four subtypes of ON-OFF direction-selective ganglion cells (DSGCs), each preferring motion in one of four cardinal directions. It has been reported in rabbit that the SACs on the 'null' sides of DSGCs form functional GABA (γ-aminobutyric acid)-mediated synapses, whereas those on the preferred sides do not. However, it is not known how the asymmetric wiring between SACs and DSGCs is established during development. Here we report that in transgenic mice with cell-type-specific labelling, the synaptic connections from SACs to DSGCs were of equal strength during the first postnatal week, regardless of whether the SAC was located on the preferred or null side of the DSGC. However, by the end of the second postnatal week, the strength of the synapses made from SACs on the null side of a DSGC significantly increased whereas those made from SACs located on the preferred side remained constant. Blocking retinal activity by intraocular injections of muscimol or gabazine during this period did not alter the development of direction selectivity. Hence, the asymmetric inhibition between the SACs and DSGCs is achieved by a developmental program that specifically strengthens the GABA-mediated inputs from SACs located on the null side, in a manner not dependent on neural activity.