Changes In GABAergic Activity Research Articles

Maternal separation and its developmental consequences on anxiety and parvalbumin interneurons in the amygdala

The early postnatal period represents an exceptionally vulnerable phase for the development of neurobiological alterations, aberrant behavior, and psychiatric disorders. Altered GABAergic activity in the hippocampus and the amygdala have been identified in humans diagnosed with depression or anxiety disorders, as well as in respective animal models. Changes in GABAergic activity can be visualized by immunohistochemical staining of parvalbumin (PV) protein. Therewith, alterations in PV intensity as well as in the integrity of the perineural net surrounding PV positive (PV+) interneurons have been reported as consequences of early stress. In the current study, maternal separation (MS) was used to induce early life stress. Female and male Sprague–Dawley rats were subjected to MS over 4 h from postnatal days 2–20. Then, anxiety behavior and PV+ interneurons in the amygdala were analyzed using immunohistochemistry in adolescence or adulthood. MS induced increased anxiety behavior in the marble-burying test in adolescence as well as in the elevated plus maze in adulthood. No effect of sex was found. Concerning alterations of parvalbumin expression in the amygdala, a trend towards a lower number of parvalbumin-positive inhibitory interneurons was shown in the amygdala after MS in adolescence, with no differences in the total number of cells. The current study offers a developmental perspective, suggesting that the kind of anxiety behavior expressed by rats following MS changes over time from active to passive avoidance, indicating that effects of MS are highly dependent on developmental state. Moreover, a cell-type-specific effect of MS on the cellular composition of the amygdala is discussed. The presented study demonstrates the long-lasting consequences of early stress on behavior, offers a possible neurobiological correlate, and discusses possible mediators in the development of these alterations.

P195. Impaired motor learning in older adults-concepts of underlying mechanisms and strategies for supporting impaired functions

Introduction The aging population is facing important challenges associated to impairments in cognitive abilities including sensorimotor functions. In our daily life the acquisition and long-term retention of motor skills play a crucial role for the appropriate implementation of motor acts, such as practicing sport or the use of modern communication tools. Notably, motor cortical plasticity is altered in older adults (OA) due to changes in neurotransmission and synaptic functioning. Changes in GABAergic activity and its modulatory capacity has been described, as well as diminished LTP-like mechanisms contributing to associative plasticity and motor memory formation. Strong interest lies in the understanding of age-associated mechanisms underlying impairment of motor performance and motor learning in old and in possible ways of ameliorating age-related deficits in these domains. Methods Experiment 1: We investigated the process of learning of sequential finger tapping in a group of 15 healthy OA (73.9 ± 5.9 years ± standard deviation [SD]) and compared to 15 healthy young subjects (24.4 ± 3.5 SD). The learning process was accompanied by double-pulse transcranial magnetic stimulation (dp-TMS) in order to investigate intracortical effects during the learning process reflecting activity of GABAergic neurotransmission. The task was performed during 5 consecutive training days, with 3 follow-up time points on day 10, 20 and 60. Experiment 2 : In a subsequent experiment, we investigated the effects of transcranial direct current stimulation (tDCS) in a group of 28 healthy OA aged 72.0 ± 5.4 SD. tDCS provides the possibility to modulate cortical excitability and neuroplasticity. We tested the hypothesis that tDCS in combination with training will enhance the effect of skill acquisition in OA. In our double-blind, placebo controlled study tDCS was applied to the motor cortex, contralateral to the training performing hand. Either anodal or placebo/sham stimulation was applied for 20 min while subjects underwent the same training as mentioned above. Results Experiment 1: Analyses revealed impaired skill acquisition in the OA group in relation to the young group during training period (pMOVE). The group of young healthy subjects showed learning related changes of SICI MOVE towards an enhanced event-related disinhibition. This was not the case for OA. Experiment 2: The group receiving real stimulation showed a different learning curve in the 5 days of training with significantly enhanced skill acquisition compared to the sham group ( p = 0.044), a behavioral effect still apparent 60 days after interventions. Conclusions Motor skill acquisition was impaired in healthy older subjects, this effect was mainly driven by a reduction in offline effects. Furthermore, tDCS can ameliorate age-related deficits in the acquisition of a novel motor skill, offering a promising interventional strategy to address age-related cognitive deficits.

Behavioral deficit and decreased GABA receptor functional regulation in the cerebellum of epileptic rats: Effect of Bacopa monnieri and bacoside A

In the present study, the effects of Bacopa monnieri and its active component, bacoside A, on motor deficit and alterations of GABA receptor functional regulation in the cerebellum of epileptic rats were investigated. Scatchard analysis of [3H]GABA and [3H]bicuculline in the cerebellum of epileptic rats revealed a significant decrease in Bmax compared with control. Real-time polymerase chain reaction amplification of GABAA receptor subunits—GABAAά1, GABAAά5, and GABAAδ—was downregulated (P<0.001) in the cerebellum of epileptic rats compared with control rats. Epileptic rats exhibit deficits in radial arm and Y-maze performance. Treatment with B. monnieri and bacoside A reversed these changes to near-control levels. Our results suggest that changes in GABAergic activity, motor learning, and memory deficit are induced by the occurrence of repetitive seizures. Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity, motor learning, and memory deficit.

5-HT 2 receptor subtypes mediate different long-term changes in GABAergic activity to parasympathetic cardiac vagal neurons in the nucleus ambiguus

Serotonin (5-HT), and in particular 5-HT 2 receptors, play an important role in cardiorespiratory function within the brainstem. In addition, abnormalities in the 5-HT system have been implicated in many cardiorespiratory disorders, including sudden infant death syndrome. However, little is known about the mechanisms of action of 5-HT 2 receptors in altering the activity of parasympathetic cardiac neurons in the brainstem. In this study we examined the effects of activation of different subtypes of 5-HT 2 receptors on spontaneous and respiratory-evoked GABAergic neurotransmission to cardioinhibitory vagal neurons within the nucleus ambiguus as well as rhythmic fictive inspiratory-related activity in rats. A single application of α-Me-5-hydroxytryptamine maleate (α-Me-5-HT), a 5-HT 2 receptor agonist, did not significantly alter the frequency of spontaneous or respiratory-evoked GABAergic inhibitory postsynaptic currents (IPSCs) in cardiac vagal neurons. However, repetitive successive applications of α-Me-5-HT elicited a long-lasting (≥1 h) decrease in the frequency of spontaneous as well as inspiratory-related GABAergic IPSCs to cardiac vagal neurons. This study demonstrates multiple, but not single applications of the 5-HT 2 receptor agonist α-Me-5-HT caused a long-lasting inhibition of both spontaneous and fictive inspiratory-related GABAergic neurotransmission to CVNs, which can be prevented by the 5-HT 2B receptor antagonist SB204741, but persisted with the 5-HT 2A/2C receptor antagonist ketanserin. The 5-HT 2 receptor agonist α-Me-5-HT also reversibly and transiently excited central fictive inspiratory activity, which was abolished by ketanserin, but was unaffected by the 5-HT 2B receptor antagonist SB204741.

Changes in [ 3H]zolpidem and [ 3H]Ro 15-1788 binding in rat globus pallidus and substantia nigra pars reticulata following a nigrostriatal tract lesion

Changes in GABA A receptor α 1 subunit gene expression occur in the globus pallidus and substantia nigra pars reticulata following lesions of the nigrostriatal tract. To determine whether these changes are translated at the protein level, we performed quantitative autoradiography with the α 1 selective ligand, [ 3H]zolpidem, and the non-selective benzodiazepine site ligand, [ 3H]Ro 15-1788. Binding of both [ 3H]zolpidem and [ 3H]Ro 15-1788 was significantly increased in the substantia nigra pars reticulata (13.5±4.1 and 26.3±2.9%, respectively) and significantly reduced in the globus pallidus (20.9±0.8 and 18.3±1.3%, respectively). These changes in α 1 subunit protein expression may help to compensate for the pathological changes in GABAergic activity that occur after striatal dopamine depletion.

Effect of unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway on GABA A receptor subunit gene expression in the rodent basal ganglia and thalamus

In Parkinson's disease, changes in GABAergic activity occurring downstream of the striatal dopamine loss are accompanied by reciprocal changes in GABA A receptor binding, the underlying molecular mechanisms for which are unknown. This study examined whether changes in expression of the genes encoding known GABA A receptor subunits (α 1–4, β 1–3, γ 1–3 and δ) could account for this receptor plasticity using a rodent model of Parkinson's disease with a 6-hydroxydopamine-induced nigrostriatal lesion. Analysis of autoradiograms of the basal ganglia and thalamus revealed changes in expression of only four of the 11 subunits studied. Expression of α 1 and β 2 subunit genes was altered in a parallel manner following a 6-hydroxydopamine lesion; messenger RNA levels for both were significantly increased in the substantia nigra pars reticulata (11±4% and 17±1%, respectively), and significantly reduced in the globus pallidus (18±3% and 16±3%, respectively) and parafascicular nucleus (19±3% and 16±5%, respectively). Smaller changes in the messenger RNA levels encoding the α 1 subunit in the lateral amygdala (8±1% decrease) and the α 4 and γ 2 subunits in the striatum (10±2% and 6±1% increase, respectively) were also observed. No changes in expression were noted for any other subunits in any region studied. Clearly, both region- and subunit-specific regulation of GABA A receptor subunit gene expression occurs following a nigrostriatal tract lesion. The changes in expression of the α 1 and β 2 subunit genes probably contribute to the documented changes in GABA A receptor binding following striatal dopamine depletion. Moreover, they provide a molecular basis by which the pathological changes in GABAergic activity in Parkinson's disease may be partially compensated.

Behavioral correlates of a progressive dysfunctioning of the deeper layers of the colliculus superior: Effects of picrotoxin

Intracaudate injections of relatively high doses of apomorphine produce a regression in motor behavior of cats collecting food pellets in a treadmill design (25). It has been hypothetized that this regression is partly due to functional disturbances in brain regions receiving (in)directly striatal output signals. In view of this hypothesis it was investigated whether experimentally induced changes in GABAergic activity within the deeper layers of the colliculus superior, which is a second order output station of the caudate nucleus, are also able to elicit a regression in motor behavior. Therefore, motor behavior of cats was tested in the treadmill paradigm before and after intracollicular injections of the GABA antagonist picrotoxin. Picrotoxin produced dose-dependently a regression in motor behavior which was comparable to that elicited by intrastriatally injected apomorphine. The noted effects were GABA-specific since muscimol attenuated the picrotoxin-induced regression. The present data are discussed in view of a model for a hierarchical organization of the brain.