[Photodynamic therapy in Germany-Quo vadis?] / Photodynamische Therapie in Deutschland ­ Quo vadis?

BACKGROUND: Photodynamic therapy (PDT) was originally approved for the treatment of neovascular age-related macular degeneration (nAMD) and secondary choroidal neovascularization in myopia (mCNV). In addition, it is used as an off-label treatment in patients with choroidal hemangioma, polypoidal choroidal vasculopathy (PCV), and central serous chorioretinopathy (CSC). OBJECTIVE: To track the development of PDT treatment numbers in Germany between 2006 and 2021 and to investigate the composition of the therapeutic indications. METHODS: In this retrospective study the quality reports of German hospitals were evaluated in the period from 2006 to 2019 and the number of PDTs performed was recorded. In addition, the range of indications for PDT was determined exemplarily for the Eye Center at Medical Center, University of Freiburg and the Eye Center at St. Franziskus Hospital in Münster between 2006 and 2021. Finally, the estimated prevalence of CSC and an estimate of cases requiring treatment were used to calculate the number of patients in need of PDT treatment in Germany. RESULTS: The number of PDTs performed in Germany decreased from 1072 in 2006 to 202 in 2019. While PDT was used in 86% of cases in patients with nAMD and in 7% of cases with mCNV in 2006, it was mainly performed in patients with CSC (70%) and choroidal hemangiomas (21%) from 2016 to 2021. With an estimated incidence of CSC of 1:10,000 and assuming that 16% of patients develop chronic CCS requiring treatment, approximately 1330 PDTs would need to be performed per year in Germany for patients with newly diagnosed chronic CSC alone. CONCLUSION: The decreasing numbers of PDT treatment performed in Germany is mainly due to a change to intravitreal injections as the preferred treatment for nAMD and mCNV. As PDT is currently the recommended treatment of choice for chronic CSC, an underprovision of PDT in Germany can be assumed. To enable an appropriate treatment for patients, a reliable verteporfin production, a simplified approval process by health insurance companies and a close cooperation between ophthalmologists in private practice and larger centers are urgently needed.

Long-term follow-up of intraocular pressure and pressure-lowering medication in patients following Excimer laser trabeculotomy.

BACKGROUND: Excimer laser trabeculotomy (ELT) is a minimally invasive procedure to lower the intraocular pressure (IOP) via a photo-ablative laser that is applied to the trabecular meshwork. With this procedure, it is possible to improve the outflow of the aqueous humor. Until now, a limited number of studies examining mostly relatively small sample sizes with midterm follow-up exist. We therefore present the analysis of a large ELT cohort in a long-term follow-up. METHODS: We recorded data from 580 patients who underwent ELT or combined ELT with cataract surgery at our institution from November 2000 until March 2011. A total of 512 patients with primary open angle glaucoma (POAG), pseudoexfoliation glaucoma (PEX), and ocular hypertension (OHT) were included in the analysis. At every follow-up examination, the usage of IOP-lowering medication and the IOP were recorded. Failure criteria were defined as the need for another surgical glaucoma procedure, when the IOP was not 21 mmHg or less and a reduction of 20% from the baseline was not achieved with (qualified success) or without (absolute success) additional medication. Statistical analysis was done using Kaplan-Meier analysis and Cox regression. RESULTS: Four hundred twenty-eight patients underwent combined cataract and ELT surgery, and 84 underwent solitary ELT surgery. After a median follow-up time of 656 days, 87% (combined surgery) and 66% (ELT) of the patients did not have to undergo another IOP-lowering intervention; 47/31% were classified as a qualified success and 31/11% as a complete success. The IOP-lowering medication, however, could not be significantly reduced within that time period. CONCLUSION: Especially when combined with cataract surgery, ELT is a feasible minimally invasive procedure to lower the IOP on a mid- to long-term basis. Over the long term, however, IOP-lowering medication could not be reduced.

[Alterations in intraocular pressure and the CorVis parameters after LASIK]. / Änderung des Augeninnendrucks und der CorVis-Parameter nach LASIK.

INTRODUCTION: The reduction of corneal thickness following laser-assisted in-situ keratomileusis (LASIK) requires a correction of intraocular pressure (IOP) measurements. The corneal visualization Scheimpflug technology (CorVis ST, Oculus, Wetzlar, Germany) not only measures the IOP and central corneal thickness (CCT) but also determines 10 additional corneal parameters, such as the time to first and second applanation and velocity. Besides CCT we compared various corneal parameters before and after LASIK in order to detect possible correlations and to correct IOP measurements. METHODS: Measurements with CorVis ST were made before and after LASIK in 45 myopic patients (45 left eyes). We compared the IOP and CorVis ST parameters using a paired t­test before and after LASIK and corrected for possible correlations in a multifactorial linear model. Finally, we correlated the changes in IOP to changes in biomechanical parameters. RESULTS: We observed a direct correlation between the IOP measurements and the corneal thickness. The IOP was underestimated by 0.039 mm Hg per micrometer in reduction of corneal thickness. The multifactorial linear model showed a correlation of IOP change to A2 velocity and the radius of applanation. CONCLUSION: Surgical thinning of the central cornea via LASIK demonstrated a direct correlation between corneal thickness and IOP measurements using the CorVis ST technique. Postoperative changes of the A2 velocity and the applanation radius also had a statistically significant influence on post-LASIK IOP measurements. Our findings could be useful to obtain more precise post-LASIK IOP measurements.

[Fusarium keratitis with dramatic outcome]. / Fusarienkeratitis mit dramatischem Ausgang.

BACKGROUND: Fungal keratitis is much less common in Europe than in Asia. Antifungal therapy can be applied topically as well as systemically and in advanced situations surgical intervention can become necessary. CASE REPORT: We present the case of a 60-year-old woman who suffered from Fusarium keratitis that showed progression to endophthalmitis following contact lens wearing. Due to numerous resistances against antimycotic drugs the eye had to be enucleated to prevent the pathogens from spreading. Histologically, major inflammatory activity could be detected but no causative organism could be found. The failure to detect a pathogen was in clear contrast to the clinical findings and was interpreted as being an overreaction of the immune response even after the Fusarium had been destroyed. CONCLUSION: If a fungal infection of the cornea is suspected, antimycotic therapy should be initiated as early as possible. In cases involving highly resistant pathogens the eye cannot always be saved.

[Individualization of exercise load control for inpatient cardiac rehabilitation. Development and evaluation of a HRV-based intervention program for patients with ischemic heart failure]. / Individualisierung der Belastungssteuerung in der kardiologischen stationären Rehabilitation. Entwicklung und Evaluation eines HRV-gesteuerten Interventionsprogramms für Patienten mit ischämisch bedingter Herzinsuffizienz.

BACKGROUND: The effective use of rehabilitation programs is of primary importance in order to improve the physical performance of cardiac disease patients. A modular program has been developed which is intended to structure and individualize conventional, exercise-based rehabilitation programs according to the individual needs and physical condition of each patient. The individualization of the program is based on detailed diagnostics before patients enter the program and daily measurements of heart rate variability (HRV) during cardiac rehabilitation. METHODS: A total of 30 patients with ischemic heart disease were randomly assigned either to the intervention group (IG), completing the modular individualized rehabilitation program [n=15, mean age 54.4±4.2 years and mean left ventricular ejection fraction (LVEF) 28.53±6.25%) or to the control group (CG) taking part in the conventional rehabilitation program (n=15, mean age 56.4±4.4 years and mean LVEF 27.63±5.62). Before and after the intervention, cardiorespiratory fitness was assessed by measurement of maximal oxygen consumption (relative VO2max) during bicycle ergometry and the 6-minute walk test (6-MWT). Pre-post comparisons of cardiorespiratory fitness indicators were used to evaluate the effectiveness of the rehabilitation program. In addition to the results of the basic clinical investigations and the cardiorespiratory testing, results of standardized HRV measurements of 10 min at morning rest served as criteria for program individualization. RESULTS: The relative VO2max increased significantly (p<0.05) in the IG whereas no change was found in the CG. Similar results were found for maximum power output during bicycle ergometry (p<0.01) and for 6-MWT distance (p<0.001). Although patients in the IG completed less aerobic exercise sessions than those in the CG (p<0.001) the physical performance of the IG improved significantly. DISCUSSION: The results prove the effectiveness and efficacy of the modular individualized rehabilitation program. They further suggest the need for an individual program matrix instead of a maximum performance matrix in cardiac rehabilitation. Individualization should be based on clinical and performance diagnostics before and accompanying assessments of training condition, e.g. by HRV measurements, during rehabilitation programs. Each patient should only perform those intervention programs which match the results of the basic clinical investigation and additional analyses during rehabilitation.

[Hermansky-Pudlak syndrome]. / Hermansky-Pudlak-Syndrom.

A 1-year-old female child suffering from nystagmus and abnormal head posture (AHP) was presented by the parents in our clinic. The family history revealed the presence of von Willebrand's disease in both parents. General examination showed a female child with light blond colored skin accompanied by black-haired parents. Physical and ophthalmic examination revealed nystagmus, AHP and oculocutaneous albinism. The molecular genetic analysis showed a mutation in the HPS-1 gene which confirmed the suspected diagnosis of Hermansky-Pudlak syndrome (HPS). Of clinical significance, patients with HPS commonly have hemorrhagic diathesis, granulomatous colitis or restrictive lung fibrosis. A detailed full medical history, ophthalmic examination as well as genetic analyses are essential in establishing the diagnosis of HPS. Treatment includes correcting refraction anomalies with spectacles or contact lenses, prescription of tinted glasses or surgical correction of the AHP. An internal medical consultation is also necessary for the management of other associated symptoms, such as hemorrhagic diathesis.

Fuctional outcome after open and arthroscopic bankart repair for traumatic shoulder instability.

PURPOSE: Both open and arthroscopic Bankart repair are established procedures in the treatment of anterior shoulder instability. While the open procedure is still considered as the "golden standard" functional outcome is supposed to be better in the arthroscopic procedure. The aim of this retrospective study was to compare the functional outcome between open and arthroscopic Bankart repair. MATERIAL AND METHODS: In 199 patients a Bankart procedure with suture anchors was performed, either arthroscopically in presence of an detached, but not elongated capsulolabral complex (40) or open (159). After a median time of 31 months (12 to 67 months) 174 patients were contacted and agreed to follow-up, 135 after open and 39 after arthroscopic Bankart procedure. RESULTS: Re-dislocations occurred in 8% after open and 15% after arthroscopic Bankart procedure. After open surgery 4 of the 11 re-dislocations occurred after a new adequate trauma and 1 of the 6 re-dislocations after arthroscopic surgery. Re-dislocations after arthroscopic procedure occurred earlier than after open Bankart repair. An external rotation lag of 20 degrees or more was observed more often (16%) after open than after arthroscopic surgery (3%). The Rowe score demonstrated "good" or "excellent" functional results in 87% after open and in 80% patients after arthroscopic treatment. CONCLUSION: In this retrospective investigation the open Bankart procedure demonstrated good functional results. The arthroscopic treatment without capsular shift resulted in a better range of motion, but showed a tendency towards more frequently and earlier recurrence of instability. Sensitive patient selection for arthroscopic Bankart repair is recommended especially in patients with more than five dislocations.

Columnar organization of dendrites and axons of single and synaptically coupled excitatory spiny neurons in layer 4 of the rat barrel cortex.

Cortical columns are the functional units of the neocortex that are particularly prominent in the "barrel" field of the somatosensory cortex. Here we describe the morphology of two classes of synaptically coupled excitatory neurons in layer 4 of the barrel cortex, spiny stellate, and star pyramidal cells, respectively. Within a single barrel, their somata tend to be organized in clusters. The dendritic arbors are largely confined to layer 4, except for the distal part of the apical dendrite of star pyramidal neurons that extends into layer 2/3. In contrast, the axon of both types of neurons spans the cortex from layer 1 to layer 6. The most prominent axonal projections are those to layers 4 and 2/3 where they are largely restricted to a single cortical column. In layers 5 and 6, a small fraction of axon collaterals projects also across cortical columns. Consistent with the dense axonal projection to layers 4 and 2/3, the total number and density of boutons per unit axonal length was also highest there. Electron microscopy combined with GABA postimmunogold labeling revealed that most (>90%) of the synaptic contacts were established on dendritic spines and shafts of excitatory neurons in layers 4 and 2/3. The largely columnar organization of dendrites and axons of both cell types, combined with the preferential and dense projections within cortical layers 4 and 2/3, suggests that spiny stellate and star pyramidal neurons of layer 4 serve to amplify thalamic input and relay excitation vertically within a single cortical column.

Hippocampal Cajal-Retzius cells project to the entorhinal cortex: retrograde tracing and intracellular labelling studies.

Cajal-Retzius (CR) cells are characteristic horizontally orientated, early-generated transient neurons in the marginal zones of the neocortex and hippocampus that synthesize the extracellular matrix protein reelin. They have been implicated in the pathfinding of entorhino-hippocampal axons, but their role in this process remained unclear. Here we have studied the axonal projection of hippocampal CR cells. Following injection of the carbocyanine dye DiI into the entorhinal cortex of aldehyde-fixed rat embryos and young postnatal rats, neurons in the outer molecular layer of the dentate gyrus and stratum lacunosum-moleculare of the hippocampus proper with morphological characteristics of CR cells were retrogradely labelled. In a time course analysis, the first retrogradely labelled CR cells were observed on embryonic day 17. This projection of hippocampal CR cells to the entorhinal cortex was confirmed by retrograde tracing with Fast Blue in new-born rats and by intracellular biocytin filling of CR cells in acute slices from young postnatal rat hippocampus/entorhinal cortex and in entorhino-hippocampal slice cocultures using infrared videomicroscopy in combination with the patch-clamp technique. In double-labelling experiments CR cells were identified by their immunocytochemical staining for reelin or calretinin, and their interaction with entorhino-hippocampal axons labelled by anterograde tracers was analysed. Future studies need to investigate whether this early transient projection of hippocampal CR cells to the entorhinal cortex is used as a template by the entorhinal axons growing to their target layers in the hippocampus.

Reliable synaptic connections between pairs of excitatory layer 4 neurones within a single 'barrel' of developing rat somatosensory cortex.

1. Dual whole-cell recordings were made from pairs of synaptically coupled excitatory neurones in the 'barrel field' in layer (L) 4 in slices of young (postnatal day 12-15) rat somatosensory cortex. The majority of interconnected excitatory neurones were spiny stellate cells with an asymmetrical dendritic arborisation largely confined to a single barrel. The remainder were star pyramidal cells with a prominent apical dendrite terminating in L2/3 without forming a tuft. 2. Excitatory synaptic connections were examined between 131 pairs of spiny L4 neurones. Single presynaptic action potentials evoked unitary EPSPs with a peak amplitude of 1.59 +/- 1.51 mV (mean +/- s. d.), a latency of 0.92 +/- 0.35 ms, a rise time of 1.53 +/- 0.46 ms and a decay time constant of 17.8 +/- 6.3 ms. 3. At 34-36 C, the coefficient of variation (c.v.) of the unitary EPSP amplitude was 0. 37 +/- 0.16 and the percentage of failures to evoke an EPSP was 5.3 +/- 7.8 %. The c.v. and failure rate decreased with increasing amplitude of the unitary EPSP. 4. Postsynaptic glutamate receptors in spiny L4 neurones were of the AMPA and NMDA type. At -60 mV in the presence of 1 mM Mg2+, NMDA receptors contributed 39.3 +/- 12.5 % to the EPSP integral. In Mg2+-free solution, the NMDA receptor/AMPA receptor ratio of the EPSC was 0.86 +/- 0.64. 5. The number of putative synaptic contacts established by the projection neurone with the target neurone varied between two and five with a mean of 3.4 +/- 1.0 (n = 11). Synaptic contacts were exclusively found in the barrel in which the cell pair was located and were preferentially located on secondary to quarternary dendritic branches. Their mean geometric distance from the soma was 68.8 +/- 37.4 microm (range, 33.4-168.0 microm). The number of synaptic contacts and mean EPSP amplitude showed no significant correlation. 6. The results suggest that in L4 of the barrel cortex synaptic transmission between spiny neurones is largely restricted to a single barrel. The connections are very reliable, probably due to a high release probability, and have a high efficacy because of the compact structure of the dendrites and axons of spiny neurones. Intrabarrel connections thus function to amplify and distribute the afferent thalamic activity in the vertical directions of a cortical column.

Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning.

Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

Specialized electrophysiological properties of anatomically identified neurons in the hilar region of the rat fascia dentata.

Because of their strategic position between the granule cell and pyramidal cell layers, neurons of the hilar region of the hippocampal formation are likely to play an important role in the information processing between the entorhinal cortex and the hippocampus proper. Here we present an electrophysiological characterization of anatomically identified neurons in the fascia dentata as studied using patch-pipette recordings and subsequent biocytin-staining of neurons in slices. The resting potential, input resistance (RN), membrane time constant (taum), "sag" in hyperpolarizing responses, maximum firing rate during a 1-s current pulse, spike width, and fast and slow afterhyperpolarizations (AHPs) were determined for several different types of hilar neurons. Basket cells had a dense axonal plexus almost exclusively within the granule cell layer and were distinguishable by their low RN, short taum, lack of sag, and rapid firing rates. Dentate granule cells also lacked sag and were identifiable by their higher RN, longer taum, and lower firing rates than basket cells. Mossy cells had extensive axon collaterals within the hilus and a few long-range collaterals to the inner molecular layer and CA3c and were characterized physiologically by small fast and slow AHPs. Spiny and aspiny hilar interneurons projected primarily either to the inner or outer segment of the molecular layer and had a dense intrahilar axonal plexus, terminating onto somata within the hilus and CA3c. Physiologically, spiny hilar interneurons generally had higher RN values than mossy cells and a smaller slow AHP than aspiny interneurons. The specialized physiological properties of different classes of hilar neurons are likely to be important determinants of their functional operation within the hippocampal circuitry.

Interneurons in the stratum lucidum of the rat hippocampus: an anatomical and electrophysiological characterization.

The anatomical and electrophysiological properties of neurons in the stratum lucidum of the CA3 subfield of the hippocampus were examined by using patch-pipette recordings combined with biocytin staining. This method facilitated the analysis of the morphological features and passive and active properties of a recently described class of spiny neurons in the stratum lucidum, as well as aspiny neurons in this region. Some, but not all, synaptic inputs of both types of neurons were found to arise from the mossy fiber system. The axons of spiny neurons in the stratum lucidum were heavily collateralized, terminating primarily in the stratum lucidum and stratum radiatum of CA3, and to a lesser extent in the stratum pyramidale and stratum oriens. Only a few axonal projections were found that extended beyond the CA3 region into CA1 and the hilus. Aspiny neurons fell into two classes: those projecting axons to the stratum lucidum and stratum radiatum of CA3 and those with axon terminations mainly in the stratum pyramidale and stratum oriens. The electrophysiological properties of spiny and aspiny neurons in the stratum lucidum were similar, but on average, the aspiny neurons had significantly higher maximal firing rates and narrower action potential half-widths. The results demonstrate that a diverse population of neurons exists in the region of mossy fiber termination in area CA3. These neurons may be involved in local-circuit feedback, or feed-forward systems controlling the flow of information through the hippocampus.

A novel type of GABAergic interneuron connecting the input and the output regions of the hippocampus.

The main excitatory pathway of the hippocampal formation is controlled by a network of morphologically distinct populations of GABAergic interneurons. Here we describe a novel type of GABAergic interneuron located in the outer molecular layer (OML) of the rat dentate gyrus with a long-range forward projection from the dentate gyrus to the subiculum across the hippocampal fissure. OML interneurons were recorded in hippocampal slices by using the whole-cell patch-clamp configuration. During recording, cells were filled with biocytin for subsequent light and electron microscopic analysis. Neurons projecting to the subiculum were distributed throughout the entire OML. They had round or ovoid somata and a multipolar dendritic morphology. Two axonal domains could be distinguished: an extensive, tangential distribution within the OML and a long-range vertical and tangential projection to layer 1 and stratum pyramidale of the subiculum. Symmetric synaptic contacts were established by these interneurons on dendritic shafts in the OML and subiculum. OML interneurons were characterized physiologically by short action potential duration and marked afterhyperpolarization that followed the spike. On sustained current injection, they generated high-frequency (up to 130 Hz, 34 degrees C) trains of action potentials with only little adaptation. In situ hybridization and single-cell RT-PCR analysis for GAD67 mRNA confirmed the GABAergic nature of OML interneurons. GABAergic interneurons in the OML projecting to the subiculum connect the input and output regions of the hippocampus. Hence, they could mediate long-range feed-forward inhibition and may participate in an oscillating cross-regional interneuron network that may synchronize the activity of spatially distributed principal neurons in the dentate gyrus and the subiculum.

Submillisecond AMPA receptor-mediated signaling at a principal neuron-interneuron synapse.

Glutamatergic transmission at a principal neuron-interneuron synapse was investigated by dual whole-cell patch-clamp recording in rat hippocampal slices combined with morphological analysis. Evoked EPSPs with rapid time course (half duration = 4 ms; 34 degrees C) were generated at multiple synaptic contacts established on the interneuron dendrites close to the soma. The underlying postsynaptic conductance change showed a submillisecond rise and decay, due to the precise timing of glutamate release and the rapid deactivation of the postsynaptic AMPA receptors. Simulations based on a compartmental model of the interneuron indicated that the rapid postsynaptic conductance change determines the shape and the somatodendritic integration of EPSPs, thus enabling interneurons to detect synchronous principal neuron activity.

Septal innervation of mossy cells in the hilus of the rat dentate gyrus: an anterograde tracing and intracellular labeling study.

Mossy cells in the hilus of the rat dentate gyrus are the main cells of origin of the dentate commissural and associational projections. They project along the septotemporal axis of the dentate gyrus and may thus influence the hippocampal signal flow in a longitudinal direction. To analyze the septal innervation of these hilar neurons, anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHAL) was used in combination with intracellular labeling of mossy cells (Lucifer yellow). Anterogradely labeled septal fibers impinge on proximal and distal dendrites of hilar mossy cells but spare the cell body. In contrast, numerous aspiny hilar neurons, presumably GABAergic interneurons, receive a septal innervation on their somata and proximal primary dendrites. These data demonstrate that septal fibers show a specificity for the dendritic segments of hilar mossy cells. Since mossy cells project predominantly to adjacent hippocampal lamellae, the activity of adjacent portions of the dentate gyrus may be influenced by the septal input onto these neurons.

Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex.

1. Dual voltage recordings were made from pairs of adjacent, synaptically connected thick tufted layer 5 pyramidal neurones in brain slices of young rat (14-16 days) somatosensory cortex to examine the physiological properties of unitary EPSPs. Pre- and postsynaptic neurones were filled with biocytin and examined in the light and electron microscope to quantify the morphology of axonal and dendritic arbors and the number and location of synaptic contacts on the target neurone. 2. In 138 synaptic connections between pairs of pyramidal neurones 96 (70%) were unidirectional and 42 (30%) were bidirectional. The probability of finding a synaptic connection in dual recordings was 0.1. Unitary EPSPs evoked by a single presynaptic action potential (AP) had a mean peak amplitude ranging from 0.15 to 5.5 mV in different connections with a mean of 1.3 +/- 1.1 mV, a latency of 1.7 +/- 0.9 ms, a 20-80% rise time of 2.9 +/- 2.3 ms and a decay time constant of 40 +/- 18 ms at 32-24 degrees C and -60 +/- 2 mV membrane potential. 3. Peak amplitudes of unitary EPSPs fluctuated randomly from trial to trial. The coefficient of variation (c.v.) of the unitary EPSP amplitudes ranged from 0.13 to 2.8 in different synaptic connections (mean, 0.52; median, 0.41). The percentage of failures of single APs to evoke a unitary EPSP ranged from 0 to 73% (mean, 14%; median, 7%). Both c.v. and percentage of failures decreased with increasing mean EPSP amplitude. 4. Postsynaptic glutamate receptors which mediate unitary EPSPs at -60 mV were predominantly of the L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor type. Receptors of the N-methyl-D-aspartate (NMDA) type contributed only a small fraction (< 20%) to the voltage-time integral of the unitary EPSP at -60 mV, but their contribution increased at more positive membrane potentials. 5. Branching patterns of dendrites and axon collaterals of forty-five synaptically connected neurones, when examined in the light microscope, indicated that the axonal and dendritic anatomy of both projecting and target neurones and of uni- and bidirectionally connected neurones was uniform. 6. The number of potential synaptic contacts formed by a presynaptic neurone on a target neurone varied between four and eight (mean, 5.5 +/- 1.1 contacts; n = 19 connections). Synaptic contacts were preferentially located on basal dendrites (63%, 82 +/- 35 microns from the soma, n = 67) and apical oblique dendrites (27%, 145 +/- 59 microns, n = 29), and 35% of all contacts were located on tertiary basal dendritic branches. The mean geometric distances (from the soma) of the contacts of a connection varied between 80 and 585 microns (mean, 147 microns; median, 105 microns). The correlation between EPSP amplitude and the number of morphologically determined synaptic contacts or the mean geometric distances from the soma was only weak (correlation coefficients were 0.2 and 0.26, respectively). 7. Compartmental models constructed from camera lucida drawings of eight target neurones showed that synaptic contacts were located at mean electrotonic distances between 0.07 and 0.33 from the soma (mean, 0.13). Simulations of unitary EPSPs, assuming quantal conductance changes with fast rise time and short duration, indicated that amplitudes of quantal EPSPs at the soma were attenuated, on average, to < 10% of dendritic EPSPs and varied in amplitude up to 10-fold depending on the dendritic location of synaptic contacts. The inferred quantal peak conductance increase varied between 1.5 and 5.5 nS (mean, 3 nS). 8. The combined physiological and morphological measurements in conjunction with EPSP simulations indicated that the 20-fold range in efficacy of the synaptic connections between thick tufted pyramidal neurones, which have their synaptic contacts preferentially located on basal and apical oblique dendrites, was due to differences in transmitter release probability of the projecting neurones and, to a lesser extent, to differenc

Functional properties of AMPA and NMDA receptors expressed in identified types of basal ganglia neurons.

AMPA- and NMDA-type glutamate receptors (AMPARs and NMDARs) mediate excitatory synaptic transmission in the basal ganglia and may contribute to excitotoxic injury. We investigated the functional properties of AMPARs and NMDARs expressed by six main types of basal ganglia neurons in acute rat brain slices (principal neurons and cholinergic interneurons of striatum, GABAergic and dopaminergic neurons of substantia nigra, globus pallidus neurons, and subthalamic nucleus neurons) using fast application of glutamate to nucleated and outside-out membrane patches. AMPARs in different types of basal ganglia neurons were functionally distinct. Those expressed in striatal principal neurons exhibited the slowest gating (desensitization time constant tau = 11.5 msec, 1 mM glutamate, 22 degrees C), whereas those in striatal cholinergic interneurons showed the fastest gating (desensitization time constant tau = 3.6 msec). The lowest Ca2+ permeability of AMPARs was observed in nigral dopaminergic neurons (PCa/PNa = 0.10), whereas the highest Ca2+ permeability was found in subthalamic nucleus neurons (PCa/PNa = 1.17). NMDARs of different types of basal ganglia neurons were less variable in their functional properties; those expressed in nigral dopaminergic neurons exhibited the slowest gating (deactivation time constant of predominant fast component tau1 = 150 msec, 100 microM glutamate), and those of globus pallidus neurons showed the fastest gating (tau1 = 67 msec). The Mg2+ block of NMDARs was similar; the average chord conductance ratio g-60mV/g+40mV was 0.18-0.22 in 100 microM external Mg2+. Hence, AMPARs expressed in different types of basal ganglia neurons are markedly diverse, whereas NMDARs are less variable in functional properties that are relevant for excitatory synaptic transmission and neuronal vulnerability.

Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs.

Activity-driven modifications in synaptic connections between neurons in the neocortex may occur during development and learning. In dual whole-cell voltage recordings from pyramidal neurons, the coincidence of postsynaptic action potentials (APs) and unitary excitatory postsynaptic potentials (EPSPs) was found to induce changes in EPSPs. Their average amplitudes were differentially up- or down-regulated, depending on the precise timing of postsynaptic APs relative to EPSPs. These observations suggest that APs propagating back into dendrites serve to modify single active synaptic connections, depending on the pattern of electrical activity in the pre- and postsynaptic neurons.