Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on alpha-subunit isoform.

The role of subunit composition in determining intrinsic maximum activation and deactivation kinetics of GABA(A) receptor channels is unknown. We used rapid ligand application (100-micros solution exchange) to examine the effects of alpha-subunit composition on GABA-evoked activation and deactivation rates. HEK 293 cells were transfected with human cDNAs encoding alpha1beta1gamma2- or alpha2beta1gamma2-subunits. Channel kinetics were similar across different transfections of the same subunits and reproducible across several GABA applications in the same patch. Current rise to peak was at least twice as fast for alpha2beta1gamma2 receptors than for alpha1beta1gamma2 receptors (reflected in 10-90% rise times of 0.5 versus 1.0 ms, respectively), and deactivation was six to seven times slower (long time constants of 208 ms versus 31 ms) after saturating GABA applications. Thus alpha-subunit composition determined activation and deactivation kinetics of GABA(A) receptor channels and is therefore likely to influence the kinetics and efficacy of inhibitory postsynaptic currents.

[The consensual approach in geriatrics]. / L'approche consensuelle en milieu gériatrique.

Caregivers are often ill-equipped to cope with repeated verbal and physical aggression by geriatric residents with cognitive deficits. Cooperation from other members of the health care team is rarely automatic and there is little adherence to established interventions. This article offers valuable insights on patient care to caregivers who work with aggressive individuals in geriatric settings. With the consensual approach, nursing assistants and attendants who are assigned to these patients daily are able to participate in the problem-solving process. They help design the approach and willingly become stakeholders in the actions presented by the patient care plans. By the end of the process they are able to view the aggressive person as someone worthy of attention and love, rather than a disruptive element to be endured.

Redistribution of spatial representation in the hippocampus of aged rats performing a spatial memory task.

Young and old rats performed on a maze according to a forced-choice and then a spatial memory procedure either in the same or a different environment. Aged rats were slower to learn the spatial memory task when tested in the same, but not in a different, room. One interpretation of this pattern of results is that although old rats learn new rules as quickly as young rats, they show less flexibility with old rules and familiar spatial information. Impaired choice accuracy during asymptote performance suggests poor processing of trial-unique information by old rats. Spatial correlates of hippocampal CA1 and hilar cells varied with task demand: CA1 cells of aged rats showed more spatially selective place fields, whereas hilar cells showed more diffuse location coding during spatial memory, and not forced-choice, tests. Such representational reorganization may reflect a compensatory response to age-related neurobiological changes in hippocampus.

Direct evidence for diazepam modulation of GABAA receptor microscopic affinity.

Alteration of agonist affinity is a potential mechanism for pharmacological modulation of ligand-gated receptor channel function. The time course for receptor activation and current onset is determined by the combined rates for two kinetic transitions that underlie the protein confirmations for binding agonist and channel gating. Using ultrafast ligand exchange techniques, we distinguish between these previously difficult to separate events and demonstrate their independent pharmacological modulation. Diazepam, which increases apparent affinity of gamma-aminobutyric acid (GABA) to GABAA receptors, was used to examine its effects on GABA binding and ion channel gating of expressed alpha 2 beta 1 gamma 2 receptors from excised outside-out patches of acutely transfected HEK 293 cells. Diazepam increased rates of current onset evoked by low concentrations (< 1 mM) but not at saturating GABA concentrations. Furthermore, rates of current decay were not affected during brief applications of GABA, and thus, demonstrated a diazepam specific effect on ligand binding affinity and not channel gating kinetics. However, current decay during and following prolonged GABA applications were altered by diazepam in a fashion similar to that for higher concentrations of GABA which also increased receptor desensitization. These findings and analysis by computer modeling indicated that diazepam likely enhances GABA receptor currents primarily by accelerating GABA association to its receptor at the first agonist binding site. These results provide the first direct physiological evidence for pharmacological modulation of microscopic binding affinity of GABA receptors.

Spatial, movement- and reward-sensitive discharge by medial ventral striatum neurons of rats.

Previous behavioral and acute electrophysiological data have lead researchers to speculate that the nucleus accumbens integrates limbic, reward and motor information. The present study examined the behavioral correlates to single unit activity of the nucleus accumbens and surrounding ventral striatum as a means of evaluating the integrative functioning of this region in an awake animal. Medial ventral striatum (mVS) activity was recorded as rats completed multiple trials on an eight arm radial maze. Neuronal activity was found to correlate with spatial, reward- and movement-related behavioral conditions. While the majority of cells demonstrated correlates of a single type (i.e. either spatial or reward correlates), 6 cells encoded multiple correlates of different types (i.e. spatial and reward correlates). The data suggests that this integrative process can be active both at the level of the individual neuron, and at the structural level. These results are consistent with the hypothesis that the mVS integrates spatial and reward-related information, which in turn influences voluntary motor output structures in order to achieve accurate navigational behavior.

Medial septal modulation of entorhinal single unit activity in anesthetized and freely moving rats.

Reversible inactivation of the medial septal area results in a spatial memory impairment and selective disruption of hilar/CA3, but not CA1, location-specific discharge. The present study examined the possibility that such septal deafferentation produces effects on hippocampal function by altering physiological properties of the primary input and output structures for hippocampus, the entorhinal cortex and the subiculum, respectively. Single unit activity of hippocampal, entorhinal, and subicular cells was recorded before, during, and after septal injection of lidocaine in anesthetized rats. When compared to hippocampal cells, relatively few subicular and entorhinal cells showed a change in mean firing rate following septal inactivation. Entorhinal unit responses to septal inactivation (via tetracaine injection) were also examined in freely moving rats performing a spatial maze task. About one-third of entorhinal cells showed enhanced or reduced firing rates of 40% or more. Also, the spatial distribution of cells found in the superficial, but not deep, entorhinal layers became less clear following septal inactivation. Together, these data are consistent with the hypothesis that manipulation of the medial septum affects hippocampal function via its septosubicular and septo-entorhinal projections in addition to the more direct septohippocampal pathway. Since entorhinal cortical function was affected by tetracaine injection into the septum, it does not appear that direct entorhinal-CA1 afferents were primarily responsible for the maintenance of CA1 location-specific neural activity in previous septal inactivation experiments. Rather, these data are consistent with the hypothesis that the persistence of CA1 place fields was accomplished by intrahippocampal neural network operations.