Convergence of PKC-dependent kinase signal cascades on NMDA receptors.

Synaptic plasticity, or long-term potentiation (LTP), of excitatory synapses in the hippocampus contributes to learning and the establishment of spatial memories. In the CA1 region, induction of LTP enhances the function of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) because of the Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of this subtype of glutamate receptor. Entry of Ca2+, via N-methyl-D-aspartate receptors (NMDARs), during strong synaptic stimulation provides the stimulus to trigger phosphorylation of AMPARs. However, this induction also requires activation of a protein kinase C (PKC)-dependent tyrosine kinase signal cascade and a concomitant upregulation of NMDARs. This review focuses upon NMDARs as potential targets of PKC and/or of the PKC-dependent tyrosine kinase cascade. PKC, acting via the CAKbeta/Src tyrosine kinase cascade, enhances NMDAR activation and may increase the number of receptors expressed in synapses. In contrast, direct phosphorylation of NMDARs by PKC increases the sensitivity of NMDA channel inactivation to intracellular Ca2+. In CAI neurons, PKC provides a point of convergence of control of NMDARs and synaptic plasticity for a wide variety of G-protein coupled and growth factor receptors.

Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons.

gamma-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter, activates a persistent low amplitude tonic current in several brain regions in addition to conventional synaptic currents. Here we demonstrate that GABA(A) receptors mediating the tonic current in hippocampal neurons exhibit functional and pharmacological properties different from those of quantal synaptic currents. Patch-clamp techniques were used to characterize miniature inhibitory postsynaptic currents (mIPSCs) and the tonic GABAergic current recorded in CA1 pyramidal neurons in rat hippocampal slices and in dissociated neurons grown in culture. The competitive GABA(A) receptor antagonists, bicuculline and picrotoxin, blocked both the mIPSCs and the tonic current. In contrast, mIPSCs but not the tonic current were inhibited by gabazine (SR-95531). Coapplication experiments and computer simulations revealed that gabazine bound to the receptors responsible for the tonic current but did not prevent channel activation. However, gabazine competitively inhibited bicuculline blockade. The unitary conductance of the GABA(A) receptors underlying the tonic current (approximately 6 pS) was less than the main conductance of channels activated during quantal synaptic transmission (approximately 15--30 pS). Furthermore, compounds that potentiate GABA(A) receptor function including the benzodiazepine, midazolam, and anesthetic, propofol, prolonged the duration of mIPSCs and increased tonic current amplitude in cultured neurons to different extents. Clinically-relevant concentrations of midazolam and propofol caused a greater increase in tonic current compared with mIPSCs, as measured by total charge transfer. In summary, the receptors underlying the tonic current are functionally and pharmacologically distinct from quantally activated synaptic receptors and these receptors represent a novel target for neurodepressive drugs.

In CA1 pyramidal neurons of the hippocampus protein kinase C regulates calcium-dependent inactivation of NMDA receptors.

The NMDA subtype of the glutamate-gated channel exhibits a high permeability to Ca(2+). The influx of Ca(2+) through NMDA channels is limited by a rapid and Ca(2+)/calmodulin (CaM)-dependent inactivation that results from a competitive displacement of cytoskeleton-binding proteins from the NR1 subunit of the receptor by Ca(2+)/CaM (Zhang et al., 1998; Krupp et al., 1999). The C terminal of this subunit can be phosphorylated by protein kinase C (PKC) (Tingley et al., 1993). The present study sought to investigate whether PKC regulates Ca(2+)-dependent inactivation of the NMDA channel in hippocampal neurons. Activation of endogenous PKC by 4beta-phorbol 12-myristate 13-acetate enhanced peak (I(p)) and depressed steady-state (I(ss)) NMDA-evoked currents, resulting in a reduction in the ratio of these currents (I(ss)/I(p)). We demonstrated previously that PKC activity enhances I(P) via a sequential activation of the focal adhesion kinase cell adhesion kinase beta/proline-rich tyrosine kinase 2 (CAKbeta/Pyk2) and the nonreceptor tyrosine kinase Src (Huang et al., 1999; Lu et al., 1999). Here, we report that the PKC-induced depression of I(ss) is unrelated to the PKC/CAKbeta/Src-signaling pathway but depends on the concentration of extracellular Ca(2+). Intracellular applications of CaM reduced I(ss)/I(p) and occluded the Ca(2+)-dependent effect of phorbol esters on I(ss.) Moreover, increasing the concentration of intracellular Ca(2+) buffer or intracellular application of the inhibitory CaM-binding peptide (KY9) greatly reduced the phorbol ester-induced depression of I(ss). Taken together, these results suggest that PKC enhances Ca(2+)/CaM-dependent inactivation of the NMDA channel, most likely because of a phosphorylation-dependent regulation of interactions between receptor subunits, CaM, and other postsynaptic density proteins.

Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG.

In central neurons, the second messenger cGMP is believed to induce long-term changes in efficacy at glutamatergic synapses through activation of protein kinase G (PKG). Stimulating nitric oxide synthase, activating soluble guanylyl cyclase or elevating concentrations of intracellular cGMP depressed excitatory synaptic transmission in CA1 hippocampal neurons. Unexpectedly, intracellular cGMP depressed responses of AMPA receptors and inhibited excitatory postsynaptic currents in hippocampal neurons independently of phosphorylation. Our findings demonstrate that cGMP's modulation of excitatory transmission may involve a coupling of AMPA channel activity to levels of cGMP.

Reversal of the activity-dependent suppression of GABA-mediated inhibition in hippocampal slices from gamma-vinyl GABA (vigabatrin)-pretreated rats.

The antiepileptic drug, gamma-vinyl GABA (GVG, vigabatrin), is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for the breakdown of GABA. In hippocampal slices prepared from rats pretreated with either an anticonvulsant dose of GVG (1500 mg/kg) or saline, electrophysiological recordings were performed in order to examine the effects of GVG pretreatment on GABAergic neurotransmission. Although GVG had no effect on the effectiveness of GABA-mediated inhibition when elicited by a single stimulus, it reversed the activity-dependent depression of inhibition which is typically observed when inhibitory pathways are activated repetitively by a train of stimuli delivered at low frequency. Similarly, GVG pretreatment prevented the progressive decline in the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) during low-frequency stimulation of inhibitory interneurons. Thus, in slices from GVG pretreated rats, the amplitudes of both the fast and slow components of the last of a series of IPSPs evoked by a 5 Hz, 4 s train were maintained at 91.5 +/- 6.6% and 87.7 +/- 6.5%, respectively, compared to 61.1 +/- 3.9% and 57.1 +/- 5.0% in control slices. Finally, in slices from GVG pretreated rats, we observed a reduction in the ability of the GABA(B) receptor agonist, baclofen, to decrease the amplitude of monosynaptic inhibitory postsynaptic currents. These results suggest that GVG may produce its frequency-dependent actions by reducing the function of release regulating presynaptic GABA(B) autoreceptors. The frequency-dependent reinforcement of inhibition by GVG may importantly contribute to the anticonvulsant effectiveness of this compound.

Activity-dependent enhancement of hyperpolarizing and depolarizing gamma-aminobutyric acid (GABA) synaptic responses following inhibition of GABA uptake by tiagabine.

The effects of the 7-aminobutyric acid (GABA) uptake blocker tiagabine on isolated inhibitory postsynaptic potentials (IPSPs) were examined in CA1 pyramidal cells of the rat hippocampal slice preparation. The IPSPs were elicited by either single stimuli or by high frequency (100 Hz, 200 ms) stimulation (HFS) of inhibitory interneurons. Bath applied tiagabine (20 microM) produced little or no increase in the amplitude of IPSPs evoked by low (30-50 microA) or high (200-400 microA) intensity single stimuli. Only the duration of IPSPs evoked by high intensity stimuli was substantially prolonged by tiagabine, the time integral of the hyperpolarizing response being increased 3.2-fold. HFS elicited much larger fast and slow IPSPs than a single stimulus. In addition, with increments in the intensity (80-550 microA) of HFS, a GABA(A) receptor-mediated depolarizing response of progressively larger amplitude appeared between, and overlapped with, the fast and slow hyperpolarizing components of the IPSP. Tiagabine application markedly increased the GABA-mediated responses evoked by both low and high intensity HFS. Increasing the intensity of HFS enhanced the drug effect. Thus, measurements of the time integral of evoked responses showed that with weak (60 microA) HFS, tiagabine caused a 3.6-fold increase in the area of hyperpolarization while, in contrast, with strong (530 microA) HFS, tiagabine produced a 13.5-fold increase in the depolarizing actions of GABA. Our results suggest that tiagabine, a therapeutically effective anticonvulsant, may paradoxically increase, through a GABA(A) receptor-mediated mechanism, neuronal depolarization during the high frequency discharge of neurons involved in epileptiform activity.

Inhibitory nature of tiagabine-augmented GABAA receptor-mediated depolarizing responses in hippocampal pyramidal cells.

Tiagabine is a potent GABA uptake inhibitor with demonstrated anticonvulsant activity. GABA uptake inhibitors are believed to produce their anticonvulsant effects by prolonging the postsynaptic actions of GABA, released during episodes of neuronal hyperexcitability. However, tiagabine has recently been reported to facilitate the depolarizing actions of GABA in the CNS of adult rats following the stimulation of inhibitory pathways at a frequency (100 Hz) intended to mimic interneuronal activation during epileptiform activity. In the present study, we performed extracellular and whole cell recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the functional consequences of tiagabine-augmented GABA-mediated depolarizing responses. Orthodromic population spikes (PSs), elicited from the stratum radiatum, were inhibited following the activation of recurrent inhibitory pathways by antidromic conditioning stimulation of the alveus, which consisted of either a single stimulus or a train of stimuli delivered at high-frequency (100 Hz, 200 ms). The inhibition of orthodromic PSs produced by high-frequency conditioning stimulation (HFS), which was always of much greater strength and duration than that produced by a single conditioning stimulus, was greatly enhanced following the bath application of tiagabine (2-100 microM). Thus, in the presence of tiagabine (20 microM), orthodromic PSs, evoked 200 and 800 ms following HFS, were inhibited to 7.8 +/- 2.6% (mean +/- SE) and 34.4 +/- 18.5% of their unconditioned amplitudes compared with only 35.4 +/- 12.7% and 98.8 +/- 12.4% in control. Whole cell recordings revealed that the bath application of tiagabine (20 microM) either caused the appearance or greatly enhanced the amplitude of GABA-mediated depolarizing responses (DR). Excitatory postsynaptic potentials (EPSPs) evoked from stratum radiatum at time points that coincided with the DR were inhibited to below the threshold for action-potential firing. Independently of the stimulus intensity with which they were evoked, the charge transferred to the soma by excitatory postsynaptic currents (EPSCs), elicited in the presence of tiagabine (20 microM) during the large (1,428 +/- 331 pA) inward currents that underlie the DRs, was decreased on the average by 90.8 +/- 1.7%. Such inhibition occurred despite the presence of the GABAB receptor antagonist, CGP 52 432 (10 microM), indicating that GABAB heteroreceptors, located on glutamatergic terminals, do not mediate the observed reduction in the amplitude of excitatory postsynaptic responses. The present results suggest that despite facilitating the induction of GABA-mediated depolarizations, tiagabine application may nevertheless increase the effectiveness of synaptic inhibition during the synchronous high-frequency activation of inhibitory interneurons by enhanced shunting.

Acute effects of gamma-vinyl GABA (vigabatrin) on hippocampal GABAergic inhibition in vitro.

The acute effects of gamma-vinyl-GABA (GVG) on GABAergic inhibition were investigated in the hippocampal slice preparation using the paired-pulse test of inhibition during extracellular recordings. Superfusion of GVG (100-500 microM) for 60 min resulted in a concentration-dependent decrease in GABAergic inhibition. Slices superfused with higher concentrations of GVG (0.5-1 mM) were hyperexcitable as demonstrated by the appearance of multiple spikes. Binding studies showed that GVG (1 mM) had no effect on the binding of [3H]flunitrazepam or [3H]TBOB and displaced no more than 15% of specific [3H]GABA binding, which indicates that GVG-induced disinhibition is not mediated through an action at the GABAA receptor complex. Consistent with this suggestion is the finding that GVG (500 microM) had little effect on the inhibition of the orthodromically evoked CA1 population spike produced by the GABAA receptor agonist muscimol (10 microM), whereas this inhibition was considerably attenuated by the GABAA receptor antagonist, bicuculline methiodide (5 microM). The results of this study suggest that the acute actions of GVG on the GABAergic neurotransmitter system are not involved in its anticonvulsant effect.

Discharge planning: issues and challenges for gerontological nursing. A critique of the literature.

Families are rapidly becoming unpaid givers of complex care. Using McKeehan & Coulton's systems model, this critique reviews the evolution of the structure and processes of discharge planning programmes. It explores three common assumptions: discharge planning programmes are cost-effective, allow for enhancement of patients' and families' quality of life, and ensure continuity of care between hospital and community. Funds are saved due to decreased lengths of initial hospital admissions and readmission rates. However, the cost of additional hospital and community resources is rarely considered. Little evidence supports the concept that discharge planning directly affects a patient's health status. Patients and families often do not perceive the same level of benefit from discharge planning as do health professionals. Several issues surrounding research methodologies used in the reviewed studies are identified. Of particular concern is the lack of qualitative research into patients' and families' experiences. The critique concludes with an exploration of ethical issues and challenges arising from increased emphasis on cost-effective discharge planning. These include patients' rights, provision of sufficient human, social and financial resources, improved hospital-community communications, and control over hospital-developed but community-implemented programmes.

Effects of multiple sclerosis on occupational and career patterns.

UNLABELLED: The paper will examine the impact of multiple sclerosis on occupational roles and career patterns of 210 persons registered with the Vancouver Island Multiple Sclerosis Society. METHODOLOGY: 210 participants responded to a 17-item mailed questionnaire. Items pertained to participants' demographic characteristics, medical history related to MS, years of career training, occupational history and changes in employment associated with changes in physical status due to MS. FINDINGS: An initial analysis indicates that the majority of the respondents (64.8%) were 30-59 years of age, the years of greatest career development. Although 97.1% of respondents had held a job at some time in their lives, only 24% were employed on a full or part-time basis at the time of the study. The greatest decrease in employment occurred in health related professions and service industries. Disabilities and symptoms which had the greatest effect on employment were fatigue and muscle weakness. Identified work related problems included inability to work full time and inaccessible environments. The paper will discuss strategies nurses can use to assist employees with MS.

Use of community support services by elderly patients discharged from general medical and geriatric medical wards.

This descriptive study examines the use of community support services by elderly persons discharged from general and geriatric medical wards of a large acute care British teaching hospital. A convenience sample of 40 patients were interviewed at 6-week intervals over a 3-month period about their need for and use of community support services. The type of ward from which patients were discharged did not influence the use of nursing, homemaker, physician, or warden/community visitor services, hospital day care, or meals-on-wheels. Patients who used the largest number of community services, and were the most frequent users of all available services, were those who, because of their fragility, died or were readmitted to hospital within 6 weeks of discharge. All families interviewed identified a need for more information about their elderly members' illnesses and prescribed medical regimes.

Geriatric versus general medical wards: comparison of patients' behaviours following discharge from an acute care hospital.

The objective of this study was to explore, from a nursing perspective, the effectiveness of geriatric wards in preparing elderly patients for discharge from an acute care hospital. A convenience sample of 40 patients aged 70 years or older was obtained from three geriatric medical wards and two general medical wards of a large British teaching hospital. Data were collected immediately prior to discharge, and after 6 and 13 weeks following discharge. No meaningful differences were found between the two patient-groups in their ability to cope with activities of daily living following discharge. The majority of deaths and/or hospital readmissions occurred within 6 weeks of discharge. A major concern identified in both groups was patients' lack of knowledge about medications and their side-effects. A need for more effective teaching programmes for elderly patients was identified.

Implications of surgery in very elderly patients.

As the number of people more than 75 years of age increase, the demands on ambulatory day surgery, operating room, and PACU nurses will increase. Nurses recognize the changes that this "graying" patient population will force on hospitals' surgical units. There is a paucity of studies on the educational needs of operating room nursing staffs responsible for the care of elderly patients. How can these needs best be met? What additional staffing is needed to cope with the increasing numbers of older patients who do not move or respond as quickly as younger patients? Research is needed in every step of the nursing process and its application to the care of very elderly patients undergoing surgery. This frail and unstable population does not easily lend itself to empirical research design; however, findings on the impact of nursing procedures, such as prevention of postoperative joint pain and hypothermia, can increase patient safety and comfort.

Geriatric rehabilitation on an acute-care medical unit.

This study examined a geriatric rehabilitation pilot project on an acute-care medical unit. Over a 6-week period, using a 35-item geriatric rating scale and a mental assessment tool, changes in behaviours of 23 patients admitted to the geriatric rehabilitation module were compared to changes in behaviours of 10 elderly patients on a regular medical unit. The patients' demographic characteristics, their nursing and medical diagnoses, and discharge patterns were reviewed. Significant changes in behaviours of patients on the rehabilitation model included: increased ability to care for themselves, to maintain balance, and to communicate with others; decreased restlessness at night; decreased confusion; decreased incidence of incontinence; and improved social skills. The paper describes the geriatric rehabilitation programme and discusses implications for nursing of elderly patients in acute-care hospitals.

Electromyographic analysis of selected muscles during sitting push-ups. Effects of position and sex.

The purpose of this study was to determine if differences in EMG activity of the latissimus dorsi, pectoralis major and triceps brachii occurred between muscles and between the 16 male and 16 female subjects performing push-ups from three different sitting positions. Surface electrodes and associated instrumentation recorded a linear envelope during seated push-ups performed 1) in a wheelchair, 2) in a long-sit position with elbows at 90 degrees, and 3) in a long-sit position with maximum elbow flexion and shoulder abduction. Results showed that women produced greater mean EMG activity than men in all muscles at all positions. Altering the exercise position did not have a consistent effect on level of activity recorded from either sex. The study concludes that use of these exercises should be based on a knowledge of the differences in muscle activity in exercise positions for men and women before treatment objectives can be effectively accomplished.