Optimising Medications for Patients With Cancer and Multimorbidity: The Case for Deprescribing.

The majority of patients diagnosed with cancer are aged over 65 years and have two or more chronic conditions in addition to cancer and the risk of chronic conditions increases further after cancer. The presence of multimorbidity adds complexity to care, as patients' goals of care and the focus of treatment can change with a diagnosis of cancer. Multimorbidity is frequently associated with polypharmacy, the use of potentially inappropriate medications, the presence of adverse drug reactions and potential drug-drug interactions: all of which impact on health outcomes and the cost of care. Consequently, it is vital that a systematic approach is taken to regularly review cancer patients' medication regimens to ensure that they support an optimal balance of benefits with acceptable levels of harm. Several patient and clinician resources are presented to guide the process of medication review and deprescribing.

Improving care for elderly patients living with polypharmacy: protocol for a pragmatic cluster randomized trial in community-based primary care practices in Canada.

BACKGROUND: Elders living with polypharmacy may be taking medications that do not benefit them. Polypharmacy can be associated with elevated risks of poor health, reduced quality of life, high care costs, and persistently complex care needs. While many medications could be problematic, this project targets medications that should be deprescribed for most elders and for which guidelines and evidence-based deprescribing tools are available. These are termed potentially inappropriate prescriptions (PIPs) and are as follows: proton pump inhibitors, benzodiazepines, antipsychotics, and sulfonylureas. Implementation strategies for deprescribing PIPs in complex older patient populations are needed. METHODS: This will be a pragmatic cluster randomized controlled trial in community-based primary care practices across Canada. Eligible practices provide comprehensive primary care and have at least one physician that consents to participate. Community-dwelling patients aged 65 years and older with ten or more unique medication prescriptions in the past year will be included. The objective is to assess whether the intervention reduces targeted PIPs for these patients compared with usual care. The intervention, Structured Process Informed by Data, Evidence and Research (SPIDER), is a collaboration between quality improvement (QI) and research programs. Primary care teams will form interprofessional Learning Collaboratives and work with QI coaches to review electronic medical record data provided by their regional Practice Based Research Networks (PBRNs), identify areas of improvement, and develop and implement changes. The study will be tested for feasibility in three PBRNs (Toronto, Montreal, and Edmonton) using prospective single-arm mixed methods. Findings will then guide a pragmatic cluster randomized controlled trial in five PBRNs (Calgary, Winnipeg, Ottawa, Montreal, and Halifax). Seven practices per PBRN will be recruited for each arm. The analysis will be by intention to treat. Ten percent of patients who have at least one PIP at baseline will be randomly selected to participate in the assessment of patient experience and self-reported outcomes. Qualitative methods will be used to explore patient and physician experience and evaluate SPIDER's processes. CONCLUSION: We are testing SPIDER in a primary care population with complex care needs. This could provide a widely applicable model for care improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03689049 ; registered September 28, 2018.

Recruitment of local excitatory circuits in the superior colliculus following deafferentation and the regeneration of retinocollicular inputs.

The local synaptic connectivity in the superficial gray layer of the superior colliculus (SC) was assessed following retinal ganglion cell axonal regeneration through a peripheral nerve graft into the SC of Lister Hooded rats, using in vitro brain slice techniques. Repair was effected between the ipsilateral eye and SC, following bilateral lesion of optic nerves and ablation of ipsilateral occipital cortex. Deafferentation surgery alone resulted in a complete loss of synaptic potentials of extrinsic origin, once both retinal and cortical inputs were removed. Stimulation of graft insertion sites elicited synaptic responses comprising monosynaptic and network-mediated depolarising events. This activity, together with similar spontaneous bursts of depolarising events and action potential firing, was generated by the activation of non-N-methyl-D-aspartate glutamate receptors. This behaviour may reflect the development of a local recurrent synaptic connectivity following the repair surgery, as both evoked and spontaneous responses developed into large long-lasting bursts of excitatory activity when inhibition mediated by GABA receptors was blocked. These results suggest that the ultrastructural changes in the superficial layers of the SC resulting from deafferentation are reflected functionally at the synaptic level in the target structure even after repair. Such changes are likely to compromise the ability of the target structure to function normally during information processing. Therefore, although axons regenerating along peripheral nerve grafts can make functional synaptic connections, their efficacy in activating the target structure will probably be compromised by local changes in synaptic connectivity.

Group II and III metabotropic glutamate receptors and the control of the nucleus reticularis thalami input to rat thalamocortical neurones in vitro.

Intracellular recordings were made from neurones in the thalamic reticular nucleus (TRN) and ventro-basal (VB) thalamus in slices of rat midbrain in vitro. Electrical stimulation of the medial lemniscus or TRN resulted in the generation of complex synaptic potentials containing disynaptic inhibitory post-synaptic potentials (IPSPs) in VB thalamocortical neurones. Analysis of the excitatory synaptic responses in TRN neurones indicates they can produce burst output response irrespective of the level of sub-threshold membrane potential. This suggests that network-evoked IPSPs in VB thalamocortical neurones occur following a burst of TRN action potentials. Using ionotropic glutamate receptor antagonists, the activation of these disynaptic events was blocked, and the monosynaptic IPSPs that resulted from the direct activation of the TRN could be isolated. The selective Group II agonists LY354740 (1-10 microM) and N-acetyl-aspartyl-glutamate (NAAG; 100-500 microM) both caused a reversible depression of these monosynaptic TRN IPSPs without any effect on membrane potential or input resistance. Likewise, the specific Group III agonist L-2-amino-4-phosphonobutanoate (10-500 microM), but not (RS)-4-phosphonophenylglycine (1 and 30 microM) also caused a reversible depression of these IPSPs, again without any effect on membrane potential or input resistance.Thus, the IPSPs recorded in VB thalamocortical neurones, evoked by TRN activation, can be depressed by the activation of either Group II or III metabotropic glutamate receptors. This is consistent with the location of these receptor types on the presynaptic terminals of TRN axons in the VB thalamus. This raises the possibility that, during periods of intense excitatory activity, glutamate release could influence the release of GABA from TRN axon terminals in the thalamus. In addition, as NAAG is located in the axons and terminals arising from the TRN, there is the possibility that this dipeptide is also released by these terminals to control the release of GABA during periods of high activity in the TRN.

Kainate receptor (GluR5)-mediated disinhibition of responses in rat ventrobasal thalamus allows a novel sensory processing mechanism.

Kainate receptors have been studied extensively in vitro, but how they might function physiologically remains unclear. We studied kainate receptor modulation of synaptic responses in the rat ventrobasal thalamus using the novel antagonist LY382884 and the agonist ATPA (selective for GluR5-containing kainate receptors) as tools. No evidence could be found for a direct contribution of kainate receptors to responses of thalamic relay cells to lemniscal (sensory) input in thalamic slices studied with the aid of intracellular and field potential recordings, using selective AMPA and NMDA receptor antagonists and LY382884. However, the GluR5 agonist ATPA reduced the IPSPs originating from the thalamic reticular nucleus. Extracellular single-neurone recordings in anaesthetised rats showed that excitatory responses evoked by physiological vibrissa afferent stimulation were reduced by LY382884 applied iontophoretically at the recording site. This action of the antagonist was occluded when GABA receptors were blocked, indicating that the reduction in excitatory sensory responses by LY382884 is due to an action on GABAergic inhibition arising from the thalamic reticular nucleus. Further experiments showed that these actions depended on whether inhibition was evoked during activation of the excitatory receptive field rather than when inhibition was evoked from a surround vibrissa. We suggest that GluR5 is located presynaptically on inhibitory GABAergic terminals of thalamic reticular nucleus neurones, and that it is normally activated by glutamate spillover from synapses between excitatory afferents and relay neurones during physiological stimulation. We propose that this GluR5-activated disinhibition has an important novel role in extracting sensory information from background noise.

Group I metabotropic glutamate receptors (mGluRs) modulate visual responses in the superficial superior colliculus of the rat.

Group I metabotropic glutamate receptors (mGluRs) are expressed in cells in the superficial layers of the rat superior colliculus (SSC) and SSC afferents. The purpose of this study was to investigate the physiological effect of Group I mGluR activation on visual responses of SSC neurones using both in vivo and in vitro techniques. In the in vivo preparation, agonists and antagonists were applied by iontophoresis and single neurone activity was recorded extracellularly in anaesthetised rats. Application of the Group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) resulted in a reversible inhibition of the visual response. The effect of DHPG could be blocked by concurrent application of the Group I (mGluR1/mGluR5) antagonist (S)-4-carboxyphenylglycine (4CPG) or mGluR1 antagonist (+)-2-methyl-4-carboxyphenylglycine (LY367385). Application of 4CPG alone resulted in a facilitation of the visual response and this effect was not changed when the visual stimulus contrast was varied. Response habituation was observed when visual stimuli were presented at 0.5 s intervals, but this was not affected by DHPG or 4CPG. In slices of the superior colliculus, stimulation of the optic tract resulted in a field EPSP recorded from the SSC whose duration was increased in the presence of the GABA antagonists picrotoxin and CGP55845. Application of DHPG (5-100 microM) reduced the field EPSP, and this effect could be reversed by the mGluR1 antagonist LY367385 (200 microM), but not by the mGluR5 antagonist MPEP (5 microM). These data show that activation of mGluR1, but probably not mGluR5, can modulate visual responses of SSC neurones in vivo, and that this could be via presynaptic inhibition of glutamate release from either retinal or, possibly, cortical afferents.

Synaptic activation of the group I metabotropic glutamate receptor mGlu1 on the thalamocortical neurons of the rat dorsal lateral geniculate nucleus in vitro.

Intracellular recordings were made from thalamocortical neurons in slices of rat dorsal lateral geniculate nucleus in vitro, where ionotropic glutamate receptors and ionotropic and metabotropic GABA receptors had been blocked. The activation of specific metabotropic glutamate receptors by exogenous agonists and by the electrical stimulation of the corticothalamic pathway was then assessed using selective antagonists. The specific group I agonist (S)-3, 5-dihydoxyphenylglycine and the non-selective agonist (1S, 3R)-1-aminocyclo-pentane-1,3-dicarboxylic acid both caused a concentration-dependent depolarization of membrane potential. These effects were associated with an increase in the apparent input resistance, and a more robust expression of both the depolarizing sag of the voltage response and the low-threshold Ca(2+) potential and an increase in thalamocortical neuron excitability. However, group I agonists selective for the mGlu5 receptor and agonists selective for group II and III receptors did not have these effects. Consequently, these data suggested that these actions were mediated specifically by the group I mGlu1 receptor. The activation of cortical fibres, with trains of 50 stimuli at 50Hz, resulted in a two-component depolarizing response. The first part of this synaptic response and the agonist-induced depolarization of membrane potential were depressed by the novel group I receptor antagonists LY367366 and LY367385, which are active at mGlu1 receptors. However, they were not blocked by 6-methyl-2-(phenylethyl)-pyridine, a highly selective mGlu5 receptor antagonist.Thus, the membrane potential depolarization of thalamocortical neurons caused either by exogenous agonists or by the stimulation of cortical fibres resulted from the specific activation of mGlu1 but not mGlu5 receptors. This result is consistent with the location of this receptor type on the distal dendrites of thalamocortical neurons in the dorsal lateral geniculate nucleus of the thalamus.

Evaluation of agonists and antagonists acting at Group I metabotropic glutamate receptors in the thalamus in vivo.

Recordings were made from single neurones in the ventrobasal thalamus of anaesthetised rats in order to evaluate the properties of several agonists and antagonists of Group I mGlu receptors. The selective mGlu1 receptor antagonist LY367385 was found to reduce excitatory responses to iontophoretically applied ACPD and DHPG whereas the mGlu5 agonist CHPG was resistant to antagonism. The antagonists LY367366 and LY393053 reduced responses to all three agonists, but without reducing responses to NMDA or AMPA. Although AIDA was also found to reduce mGlu agonist-evoked responses, this antagonist also produced significant reductions in responses to NMDA and AMPA. These data suggest that there are functional mGlu1 and mGlu5 receptors in the thalamus. Furthermore, LY367385 is a useful tool for investigating mGlu1 functions whereas LY367366 and LY393053 have a broader spectrum of action. The usefulness of AIDA as an antagonist in physiological experiments would appear to be limited by its effects against NMDA and AMPA.

Group III metabotropic glutamate receptors control corticothalamic synaptic transmission in the rat thalamus in vitro.

1. Corticothalamic (CT) EPSPs evoked at <= 0.1 Hz were recorded from thalamocortical neurones in the rat dorsal lateral geniculate nucleus in vitro, with both GABAA and GABAB receptors blocked. 2. The group III metabotropic glutamate (mGlu) receptor agonists L-2-amino-4-phosphono-butyric acid (L-AP4) and O-phospho-L-serine (L-SOP) both caused a concentration-dependent depression of the CT EPSP. The maximum depression and EC50 values for these effects were 64.4 +/- 3.8 % and 88.0 +/- 24.7 microM for L-AP4, and 42.0 +/- 2.5 % and 958 +/- 492 microM for L-SOP, respectively (means +/- s.e.m.). Neither agonist had any effect on membrane potential or input resistance. 3. The depression of the CT EPSP caused by L-AP4 was reversed using the group III antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 1 mM), and the group II/III antagonist LY341495 (3 microM), but not using the group II antagonist (2S)-alpha-ethylglutamic acid (300 microM). The potencies of L-AP4, L-SOP and LY341495 indicate that this action of L-AP4 is mediated via mGlu7 and mGlu8 and not mGlu4 receptors. 4. Neither MAP4 nor LY341495 had any effect on the CT EPSPs evoked by 10 Hz trains of five stimuli, indicating the lack of endogenous activation of group III mGlu receptors in the thalamus during short bursts of cortical input. However, the magnitude of the depression caused by L-AP4 indicates that any physiological activation of group III mGlu receptors would have a profound effect on the CT input to the thalamus, and hence cortical control of thalamic function.

Antagonism of the mGlu5 agonist 2-chloro-5-hydroxyphenylglycine by the novel selective mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) in the thalamus.

Our previous work has shown that Group I mGlu receptors participate in thalamic sensory processing in vivo. However, unequivocal demonstration of mGlu5 participation has not been possible due to the lack of specific ligands. We have therefore made a preliminary study of the in vivo actions of the agonist (R,S)-2-Chloro-5-hydroxyphenylglycine [CHPG] and the novel mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine [MPEP] in order to characterize their suitability for functional studies. Iontophoretically administered MPEP selectively antagonized excitatory responses of single rat thalamic neurones to CHPG compared to the broad-spectrum mGlu agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate. In contrast, the established mGlu1 and mGlu5 antagonist (S)-4-carboxyphenylglycine reduced responses to both agonists. These findings are the first demonstration of an in vivo action of CHPG and its antagonism by a selective mGlu5 antagonist. Furthermore MPEP appears to be a good tool for functional studies of mGlu5.

Visual experience alters the molecular profile of NMDA-receptor-mediated sensory transmission.

N-methyl-D-aspartate (NMDA) receptors (NMDArs) may facilitate experience-dependent changes in the visual system. Early sensory experience has an influence over the production of the molecular components from which NMDArs are assembled, and thereby alters the properties of functional receptors. Using the antagonists D-2-amino-5-phosphonovalerate (AP5) and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), which have some selectivity for different variants of the NMDAr, we demonstrate that visual deprivation (by dark rearing) has functional consequences for NMDArs in the superior colliculus. An increase in the sensitivity of visual responses to AP5 in dark-reared rats indicated that NMDArs were more important for visual transmission in these individuals. We also observed a relative change in the efficacy of the antagonists against the visual responses of normal versus dark-reared rats. AP5 reduced the visual responses of both groups, but CPP was ineffective against visual responses after dark rearing. In the same neurons, CPP blocked NMDA induced activity indicating that molecular adaptations of NMDArs are specific to those synapses mediating visual activity.

Four years' experience of a senior house officer rotation in general medicine including general practice.

A four-month post in general practice was included as an option available to doctors applying for a year-long medical senior house officer (SHO) rotation since August 1993. This study sought the views of SHOs before and after undertaking the general practice post. SHOs gained an understanding of modern general practice and changed their views about certain aspects of general practice. They reported gaining a range of generic skills, which included communication, consultation, and clinical skills. These perceived benefits suggest that such experience merits wider adoption and further evaluation.

Modulation of sensory inhibition in the ventrobasal thalamus via activation of group II metabotropic glutamate receptors by 2R,4R-aminopyrrolidine-2,4-dicarboxylate.

Recordings were made from single neurones responsive to somatosensory input in the ventrobasal thalamus of the anaesthetised rat. GABAergic afferent inhibition arising from the thalamic reticular nucleus was evoked using a condition-test vibrissal stimulation paradigm. Local iontophoretic application of the group II metabotropic glutamate receptor (mGluR) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the vicinity of the recorded neurones produced a reduction of the afferent inhibition (from 78+/-3.0% to 25+/-5.3%), presumably via a presynaptic mechanism. This effect could be antagonised by LY307452, a known group II mGluR antagonist. In contrast, two selective group I mGluR agonists, (S)-3,5-dihydroxyphenylglycine (DHPG) and trans-azetidine-2,4-dicarboxylate (tADA), were without effect on the GABAergic inhibition. These data show that group II but not group I mGluRs can have a significant role in the modulation of GABAergic afferent inhibition in the ventrobasal thalamus. This could be of importance in the control of sensory discriminative processes and functions of sleep, arousal and seizure generation.

Characterization of sensory and corticothalamic excitatory inputs to rat thalamocortical neurones in vitro.

1. Using an in vitro slice preparation of the rat dorsal lateral geniculate nucleus (dLGN), the properties of retinogeniculate and corticothalamic inputs to thalamocortical (TC) neurones were examined in the absence of GABAergic inhibition. 2. The retinogeniculate EPSP evoked at low frequency (>= 0.1 Hz) consisted of one or two fast-rising (0.8 +/- 0.1 ms), large-amplitude (10.3 +/- 1.6 mV) unitary events, while the corticothalamic EPSP had a graded relationship with stimulus intensity, owing to its slower-rising (2.9 +/- 0.4 ms), smaller-amplitude (1.3 +/- 0.3 mV) estimated unitary components. 3. The retinogeniculate EPSP exhibited a paired-pulse depression of 60.3 +/- 5.6 % at 10 Hz, while the corticothalamic EPSP exhibited a paired-pulse facilitation of > 150 %. This frequency-dependent depression of the retinogeniculate EPSP was maximal after the second stimulus, while the frequency-dependent facilitation of the corticothalamic EPSP was maximal after the fourth or fifth stimulus, at interstimulus frequencies of 1-10 Hz. 4. There was a short-term enhancement of the >= 0.1 Hz corticothalamic EPSP (64.6 +/- 9.2 %), but not the retinogeniculate EPSP, following trains of stimuli at 50 Hz. 5. The >= 0.1 Hz corticothalamic EPSP was markedly depressed by the non-NMDA antagonist 1-(4-amino-phenyl)-4-methyl-7,8-methylene-dioxy-5H-2, 3-benzodiazepine (GYKI 52466), but only modestly by the NMDA antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ((RS)-CPP), and completely blocked by the co-application of GYKI 52466, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), (RS)-CPP and (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801). Likewise, the corticothalamic responses to trains of stimuli (1-500 Hz) were greatly reduced by this combination of ionotropic glutamate receptor antagonists. 6. In the presence of GYKI 52466, CNQX, (RS)-CPP and MK-801, residual corticothalamic responses and slow EPSPs, with a time to peak of 2-10 s, could be generated following trains of five to fifty stimuli. Neither of these responses were occluded by 1S,3R-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD), suggesting they are not mediated via group I and II metabotropic glutamate receptors.

Reduction of sensory and metabotropic glutamate receptor responses in the thalamus by the novel metabotropic glutamate receptor-1-selective antagonist S-2-methyl-4-carboxy-phenylglycine.

Previous work has shown that responses of thalamic neurons in vivo to the metabotropic glutamate receptor agonists 1S,3R-aminocyclopentane-1,3-dicarboxylate and S-3,5-dihydroxyphenylglycine can be reduced by a variety of phenylglycine antagonists. Responses of thalamic neurons to noxious thermal somatosensory stimuli were reduced in parallel by these antagonists, indicating that these responses are mediated by Group I metabotropic glutamate receptors (i.e. metabotropic glutamate receptor-1 and/or metabotropic glutamate receptor-5), which are known to be linked to phosphoinositol phosphate hydrolysis. The recent development of S-2-methyl-4-carboxyphenylglycine as an antagonist which is highly selective for metabotropic glutamate receptor-1 compared to metabotropic glutamate receptor-5 on human receptors expressed in AV-12 cells, now offers the possibility of discriminating between these two receptor subtypes in order to distinguish which is involved in thalamic responses. We have made recordings from single somatosensory neurons in the thalamus of the rat, and find that S-2-methyl-4-carboxy-phenylglycine is able to reduce responses of neurons to 1S,3R-aminocyclopentane-1,3-dicarboxylate, S-3,5-dihydroxyphenylglycine, and noxious stimuli without significant effect on responses to either N-methyl-D-aspartate or (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. These results suggest that excitatory responses of thalamic neurons to 1S,3R-aminocyclopentane-1,3-dicarboxylate and S-3,5-dihydroxyphenylglycine may be mediated by metabotropic glutamate receptor-1. Furthermore, the reduction of nociceptive responses by S-2-methyl-4-carboxy-phenylglycine indicates that metabotropic glutamate receptor-1 is involved in thalamic nociceptive processing and that such antagonists may have analgesic properties.

On the action of the anti-absence drug ethosuximide in the rat and cat thalamus.

The action of ethosuximide (ETX) on Na+, K+, and Ca2+ currents and on tonic and burst-firing patterns was investigated in rat and cat thalamic neurons in vitro by using patch and sharp microelectrode recordings. In thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (LGN), ETX (0.75-1 mM) decreased the noninactivating Na+ current, INaP, by 60% but had no effect on the transient Na+ current. In TC neurons of the rat and cat LGN, the whole-cell transient outward current was not affected by ETX (up to 1 mM), but the sustained outward current was decreased by 39% at 20 mV in the presence of ETX (0.25-0.5 mM): this reduction was not observed in a low Ca2+ (0.5 mM) and high Mg2+ (8 mM) medium or in the presence of Ni2+ (1 mM) and Cd2+ (100 microM). In addition, ETX (up to 1 mM) had no effect on the low-threshold Ca2+ current, IT, of TC neurons of the rat ventrobasal (VB) thalamus and LGN and in neurons of the rat nucleus reticularis thalami nor on the high-threshold Ca2+ current in TC neurons of the rat LGN. Sharp microelectrode recordings in TC neurons of the rat and cat LGN and VB showed that ETX did not change the resting membrane potential but increased the apparent input resistance at potentials greater than -60 mV, resulting in an increase in tonic firing. In contrast, ETX decreased the number of action potentials in the burst evoked by a low-threshold Ca2+ potential. The frequency of the remaining action potentials in a burst also was decreased, whereas the latency of the first action potential was increased. Similar effects were observed on the burst firing evoked during intrinsic delta oscillations. These results indicate an action of ETX on INaP and on the Ca2+-activated K+ current, which explains the decrease in burst firing and the increase in tonic firing, and, together with the lack of action on low- and high-threshold Ca2+ currents, the results cast doubts on the hypothesis that a reduction of IT in thalamic neurons underlies the therapeutic action of this anti-absence medicine.

Postnatal development of membrane properties and delta oscillations in thalamocortical neurons of the cat dorsal lateral geniculate nucleus.

The development of membrane properties, firing patterns, and delta oscillations in neurons of the cat dorsal lateral geniculate nucleus (dLGN) was investigated in vitro during the first 7 postnatal weeks. Compared with adult neurons, the resting membrane potential was more depolarized at postnatal days 1-9 (P1-P9), the input resistance was higher at P1-P7, and action potentials had a higher threshold and a smaller amplitude at P1-P3 and a longer duration at P1-P9. At P1-P3 trains longer than 200 msec were rarely observed, and trains with more than three action potentials were only present in 41% of the neurons, whereas at P1-P7 the normalized slope of the instantaneous frequencies at the first five interspike intervals was smaller than in the adult. A long-lasting (up to 6 sec) afterhyperpolarization followed a short train of action potentials in 88 and 30% of neurons at P1-P3 and P30-P32, respectively, but it was rarely observed in the adult. The low-threshold Ca2+ potential could evoke a burst of action potentials since P1. However, at P1-P7 the number of action potentials per burst was smaller (range, one to five), and at P1-P9 their maximum instantaneous frequency was lower (<190 Hz) than in the adult (range, six to eight, and 344 Hz, respectively). No delta oscillations were observed until P17, and their frequency (0.36 Hz) was lower than that in the adult (1.8 Hz). The percentage of neurons displaying delta oscillations and their frequency reached adult values by the end of the seventh postnatal week, i.e., well after the maturation of the membrane properties and firing patterns (second postnatal week). In conclusion, the maturation of the electrophysiological properties of thalamocortical neurons in the cat dLGN is completed later than the retinogeniculate axon segregation (Shatz CJ, 1983), and the immaturity of the oscillatory, and not of the burst-firing, activity is a limiting factor in the development of delta waves.

Molecular genetic mapping of the mouse male sterility and histoincompatibility (mshi) mutation on proximal chromosome 10.

The recessive male sterility and histoincompatibility (mshi) mutation in the mouse generates pleiotropic effects on histocompatibility and male reproduction, while female mutants appear to be reproductively normal. We have mapped the mshi mutation to mouse Chromosome (Chr) 10 by analysis of 126 progeny from an intraspecific backcross. Our analysis both places the male sterility and histoincompatibility controlled by mshi within a 20-cM interval between the markers D10Mit51/D10Mit212 and D10Mit170 and has allowed the ordering of several other microsatellite markers on Chr 10 that were previously unresolved. The high-resolution backcross panel we describe should facilitate the isolation of more tightly linked probe sequences and, ultimately, the molecular identification of the gene or genes affected by this interesting mutation.