U-100, pH-Neutral formulation of VIAject(®) : faster onset of action than insulin lispro in patients with type 1 diabetes.

AIMS: VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). METHODS: Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. RESULTS: VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. CONCLUSIONS: This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures.

BACKGROUND AND PURPOSE: Earlier studies had demonstrated that tonic-clonic seizure-like events (SLEs) resembling electrographic correlates of limbic seizures in animals and humans can be induced in organotypic hippocampal slice cultures (OHSCs). We have explored OHSCs for their suitability to serve as in vitro models of limbic seizures for studying seizure mechanisms and screening new antiepileptic compounds. EXPERIMENTAL APPROACH: OHSCs were cultivated according to the interface method. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering magnesium concentration or by applying the potassium channel blocker 4-aminopyridine. The effects of standard antiepileptic drugs (AEDs), carbamazepine, phenytoin, valproic acid, clonazepam, diazepam and phenobarbital sodium on SLEs were analysed. KEY RESULTS: In more than 93% of OHSCs, AEDs did not prevent the induction of SLEs or stop ongoing seizure activity even when toxic concentrations were applied. This pharmacoresistance was independent of the method of seizure provocation, postnatal age at explantation (P2-P10) and cultivation time in vitro (2 months). SLEs were reversibly blocked by glutamate antagonists or the GABA(A)-agonist muscimol. CONCLUSIONS AND IMPLICATIONS: We present a simple to establish in vitro model of tonic-clonic SLEs that is a priori pharmacoresistant and thus has an advantage over animal models of pharmacoresistant seizures in which responders and non-responders can be sorted out only after an experiment. OHSCs could be suitable for exploring mechanisms of pharmacoresistant seizures and be used for the identification of new anticonvulsive compounds eventually effective in drug refractory epilepsy.

Attachment for infants in foster care: the role of caregiver state of mind.

The concordance between foster mothers' attachment state of mind and foster infants' attachment quality was examined for 50 foster mother-infant dyads. Babies had been placed into the care of their foster mothers between birth and 20 months of age. Attachment quality was assessed between 12 and 24 months of age, at least 3 months after the infants' placement into foster care. The two-way correspondence between maternal state of mind and infant attachment quality was 72%, kappa = .43, similar to the level seen among biologically intact mother-infant dyads. Contrary to expectations, age at placement was not related to attachment quality. Rather, concordance between maternal state of mind and infant attachment was seen for relatively late-placed babies, as well as early placed babies. These findings have two major implications. First, following a disruption in care during the first year and a half of life, babies appear capable of organizing their behavior around the availability of new caregivers. Second, these data argue for a nongenetic mechanism for the intergenerational transmission of attachment.

Exposure to violence and neighborhood affiliation among inner-city youth.

Examined the prediction of exposure to violence by neighborhood affiliation in a sample of 167 inner-city adolescents (107 girls, 60 boys) age 14 to 19 years. Measures of exposure to violence, emotional and behavioral problems, and demographic information as well as a new neighborhood affiliation measure developed specifically for adolescents were administered. Adolescents reported fairly high rates of exposure to violence, supporting other recent research. Boys reported experiencing and witnessing significantly more violence than girls. In multiple regression analyses, higher neighborhood affiliation predicted greater exposure to violence at a trend level (p = .06), even when age, sex, length of residence in one's neighborhood, and concurrent emotional and behavioral problems were controlled. These findings suggest that greater affiliation or attachment to one's neighborhood may be an important risk factor for inner-city youth that should be investigated in larger samples.

Assessing the status of research on violence-related problems among youth.

Presents results of a systematic review of abstracts on studies related to violence and youth in an effort to identify areas that have received little attention in the psychological literature and to present recommendations for future research. A total of 1,168 empirical articles on violence-related problems in youth were identified by a PsycINFO (American Psychological Association, 1980-1999) search. These articles were then classified in a multidimensional grid, allowing for comparisons among different types of articles. A review of abstracts from these articles indicated that most of the research activity has been descriptive (e.g., reviewing correlates or predictors of violence involvement) or assessment related (e.g., evaluating specific measures). Fewer articles examined the treatment or prevention of violence-related problems among youth. Further, the majority of studies pertained to direct exposure to violence (as a victim or perpetrator), with very few studies looking at the effects of witnessing violence, knowing individuals exposed to violence, or being exposed to violence through the media. Comparing treatment and prevention articles, we found that the least empirical attention was paid to the prevention of violence-related problems in youth, and not a single study was identified through this search that sought to examine the prevention of youth witnessing violence. Implications for future research agendas are discussed.

Activity-dependent development of spontaneous bioelectric activity in organotypic cultures of rat occipital cortex.

The development of spontaneous bioelectric activity (SBA) in organotypic tissue cultures (OTCs) from rat occipital cortex was studied by means of extracellular recording techniques in OTCs grown normally for 6-51 days in vitro (DIV), and in OTCs in which SBA had been silenced from DIV 4 on for 2 to 3 weeks by elevating the Mg(2+) levels in the growth medium. The proportions of spontaneously active neurones increased from about 25% at 6-14 DIV to more than 80% beyond the third week in vitro. Mature neurones discharged at shorter intervals and more vigorously than immature neurones; the developmental increase in firing rate was not significant, however. In OTCs 6-14 DIV the majority of spontaneously active neurones fired sluggishly in a regular manner. The remaining neurones fired action potentials in the form of discrete bursts resembling interictal activity in vivo. The proportions of these neurones increased from about 40% at 6-14 DIV to more than 80% beyond the third week in vitro. During development in vitro the mean burst duration increased from 3.5 s to about 8 s whereas the mean burst rate (between 0.7-1 bursts/min) remained constant. Activity-deprived neurons had low firing rates and fired action potentials in the form of discrete bursts with a mean burst rate of 0.4/min. The proportions of spontaneously active neurons, the variability of neuronal firing and the viability of the explants either were not altered by the activity blockade or had recovered to control values after 5-6 days in normal growth medium. We conclude that in OTCs of rat neocortex the absence of SBA during development in vitro delays the maturation of excitatory mechanisms responsible for the developmental increase in firing intensity. The development of burst firing modes is less affected by activity blockade.

A questionnaire to measure factors that protect youth against stressors of inner-city life.

This study reports the development of the My Life Questionnaire (MLQ), a self-report measure of factors that protect inner-city youth against stressors such as poverty, crime, and violence. An initial pool of 23 items reflecting important protective factors was developed through focus groups with inner-city youth and clinicians working with them in a school-based mental health program. Item-total correlations and factor analysis resulted in a 12-item measure containing three factors: avoiding negative peer influences, focusing on the future, and religious involvement. Scores on the MLQ were negatively correlated with behavioral problems, supporting its validity. The measure holds promise for use in clinical and research efforts with disadvantaged urban youth.

Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified.

OBJECTIVE: Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS). METHOD: Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other. RESULTS: The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement. CONCLUSIONS: Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

Formation of the corticopontine projection in a long-term culture system.

The reestablishment in vitro of the corticopontine projection was studied in organotypic co-cultures of cortex and pons of rats 0 (day of birth) - 3 days old. After 2-3 weeks in vitro, application of the lipophilic tracer DiI in the pontine explant retrogradely stained in layer V of the cortical explant pyramidal neurons which were characterized by large somata and spiny dendrites with an apical dendrite that reached upper cortical layers II/III. The projection developed only in co-cultures from rats 0-2 days old when the pontine explant was placed in close vicinity either to the white matter or the pial surface of the cortical explant. Control experiments demonstrated the specificity of the corticopontine projection in vitro by showing that the projections of the layer V pyramidal cells to the pons did not reflect a non-directed outgrowth pattern with subsequent survival of axons contacting the target explant. Our findings demonstrate that morphology and laminar position of corticopontine projection neurons in vitro are similar to those in vivo and thus support the "organotypic" nature of the explant co-culture system.

Performance of real time separation of multi-neuron recordings with a DSP32C microprocessor.

The performance of a method for sorting of waveforms in multi-neuron data (Gädicke and Albus, 1995) is evaluated by using artificial spike patterns generated by the computer and by adding to these spikes noise or free running sine waves of varying frequency and amplitude to simulate EEG-waves. The DSP32C is capable of continuously processing spikes at 183.106 Hz. In addition to real-time sorting the DSP32C also performs a running average of the spikes sorted into each class and transfers data to the host computer. The ability of the system to analyse burst of activity is determined by the FIFO memory buffer (2048 samples, or 32.768 ms at 62.5 kHz sampling rate). Adding a 50 Hz sine wave discrimination worked correctly with sine wave amplitudes of up to 2.5 times that of the smallest spike. Combining spikes with noise revealed errors of inclusion and/or exclusion of less than 0.1% provided the models spikes were determined from noiseless spikes and the spike threshold was set above the noise peak level. When noisy spikes were used to define model spikes about 4% of the smallest amplitude spikes (signal to noise ratio 3.3) were incorrectly classified. For higher amplitude spikes (signal to noise ratio > or = 5) the classification error was on average less than 1%. The artificial patterns used for performance testing are exactly defined and could be used to standardize the comparison between different sorting techniques.

Neurons in the rat occipital cortex co-expressing the substance P-receptor and GABA: a comparison between in vivo and organotypic cultures.

The morphology and the distribution of neurons expressing the NK1-receptor (NK1R) and the co-expression of gamma-aminobutyric acid (GABA) in these neurons were studied in the rat occipital cortex and in organotypic cultures (OTCs) derived from this structure. By employing immunohistochemistry, we demonstrate that the NK1R-expressing neurons are non-pyramidal neurons and co-express GABA. Some differences were noted between in vivo and OTCs. NK1R-expressing neurons in OTCs had larger somata and longer dendrites and the proportion stained with an anti-GABA-antibody (approximately 50%) was smaller than in vivo (90%). The preferential location of NK1R-expressing neurons in layers II/III and VI, seen in vivo is not present in OTCs where these neurons distribute rather homogeneously through layers II-VI. Our findings imply that in contrast to the cat and monkey, in the rat occipital cortex the effects of substance P are almost exclusively mediated via inhibitory interneurons.

Pubertal development and onset of psychosis in childhood onset schizophrenia.

In this study, pubertal development was examined for a sample of children and adolescents with childhood onset schizophrenia (COS) defined as psychosis by age 12. Developmental and psychiatric histories were obtained for 28 adolescents (mean age 14.5 +/- 2.3 years) with severe, treatment refractory COS (14 males, 14 females). Age of onset of psychosis was also examined in relation to menarche and development of secondary sex characteristics. Girls had a trend towards developing secondary sex characteristics earlier than boys (P = 0.06), consistent with North American norms. Males (N = 14) and females (N = 14) had similar age of onset of psychosis. The age of development of secondary sex characteristics was associated with onset of psychosis for girls, but this finding was driven by one outlier. There was no significant correlation between development of psychosis and menarche. Neither male nor female probands differed significantly from their well siblings or from North American norms in their age of onset of pubertal development. There was no evidence of early onset of secondary sex characteristics for this sample. Finally, there was an absence of a clear relationship between onset of psychosis and indices of sexual development for these very early onset cases.

Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison.

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia. METHODS: Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d). RESULTS: Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine. CONCLUSIONS: Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia.

BACKGROUND: Early-onset schizophrenia (first psychotic symptoms by age 12 years) has been the subject of a small number of studies, and its biological continuity with later-onset disorder has not been established. In this study quantitative anatomic brain magnetic resonance images of children and adolescents with early-onset schizophrenia were compared with those of matched controls. Brain abnormalities in childhood-onset schizophrenia were examined in relation to those reported for later-onset schizophrenics. METHODS: Anatomic brain magnetic resonance imaging scans were obtained for 21 patients (mean +/- SD age, 14.6 +/- 2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males, eight females) and 33 age-, sex-, height-, and weight-matched normal controls. Quantitative measurements were obtained for the cerebrum, anterior frontal region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus. RESULTS: Total cerebral volume and midsagittal thalamic area were smaller in the patients (analysis of variance, P = .002, and analysis of covariance, P = .03, respectively); the caudate, putamen, and globus pallidus were larger in the patients (analysis of covariance, P = .05, P = .007, and P < .001, respectively); and the lateral ventricles tended to be larger in the patients (analysis of covariance, P = .06). Globus pallidus enlargement correlated with neuroleptic exposure and with age of onset of psychosis. The magnitude of abnormalities compared with controls was similar to that reported in adult studies, although there was a trend toward relatively smaller cerebral volumes for the childhood-onset group compared with controls. CONCLUSION: Brain anatomic abnormalities in childhood-onset schizophrenia are similar to those reported for adult populations, indicating overall continuity between these rare childhood cases and the adult schizophrenia populations.

Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment.

OBJECTIVE: The effect of clozapine on striatal morphology was examined in adolescents with childhood-onset schizophrenia. METHOD: Eight adolescent patients with onset of psychosis before age 12 and eight matched comparison subjects had initial and 2-year follow-up brain magnetic resonance imaging scans. Basal ganglia and lateral ventricle volumes were measured. The patients were on a clozapine regimen during the 2-year interim. RESULTS: Caudate volume was larger in the patients at the initial scanning, decreased in the patients between scans, and did not differ significantly between the patients and the comparison subjects at the second scanning. CONCLUSIONS: Caudate enlargement in patients with childhood-onset schizophrenia who are taking typical neuroleptics appears to be secondary to medication exposure. Rescanning to examine basal ganglia morphology is indicated for these patients when they are taking an atypical neuroleptic.

Localization of AMPA-selective glutamate receptor subunits in the adult cat visual cortex.

We have studied the presence and distribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-selective glutamate receptor subunits (GluR1, 2, 3, and 4) in the adult cat visual cortical areas 17, 18, 19, and the lateral suprasylvian areas (LSA). Reverse transcription-polymerase chain reaction (RT-PCR) amplification indicated that the genes encoding GluR1, 2, 3, and 4 are expressed in these areas and Western blot analysis revealed that the size of the corresponding peptides is similar to those described in the rat brain. In situ hybridization (ISH) using digoxigenin-labeled riboprobes showed that mRNAs coding for GluR1 and GluR3 were located in cells in all layers of the areas examined and also in the underlying white matter. GluR1 mRNA was relatively abundant throughout layers II-VI while GluR3 mRNA revealed a more laminated pattern of expression, preferentially labeling cells in layers II, III, V, and VI. The distribution of AMPA-selective receptor subunit peptides was studied by immunohistochemistry using subunit specific antibodies and found to be consistent with ISH results. In addition, we observed that most of the cells strongly labeled by the anti-GluR1 antibody were non-pyramidal neurons and that intense GluR2/3 immunoreactivity was seen preferentially in pyramidal neurons. Interestingly, double-labeling experiments indicated that neurons expressing gamma-aminobutyric acid (GABA) as well as the GluR1 subunit were particularly abundant in deeper layers. The GluR4 peptide was predominantly found in a relatively low number of layer III and layer V neurons with either pyramidal or non-pyramidal morphology. Finally, the distribution of neurons expressing the various receptor subunits was similar in all the visual cortical areas studied. These findings indicate a high expression of GluR1-3 subunits in the cat visual cortex and that GluR1 and GluR2/3 subunits are particularly abundant in non-pyramidal and pyramidal neurons, respectively. In addition, the results described here provide a reference for future studies dealing with the effect of visual deprivation on the expression of this receptor type.

Childhood-onset schizophrenia: the severity of premorbid course.

OBJECTIVE: To review the premorbid histories of 23 children meeting DSM-III-R criteria for schizophrenia with onset before age 12 years and to compare these with childhood data of later-onset schizophrenics. METHOD: Premorbid features up to 1 year before onset of first psychotic symptoms were rated from hospital and clinic records, clinical interviews, rating scales, and tests. RESULTS: In keeping with previous studies, specific developmental disabilities and transient early symptoms of autism, particularly motor stereotypies, were common. Comparison with the childhood of later-onset schizophrenics showed greater delay in language development, and more premorbid speech and language disorders, learning disorders, and disruptive behavior disorders. (Sixty percent had received or were estimated to meet criteria for one or more clinical diagnoses.) CONCLUSIONS: Childhood-onset schizophrenia may represent a more malignant form of the disorder, although selection and ascertainment bias cannot be ruled out. The presence of prepsychotic language difficulties focuses attention on the importance of early temporal and frontal lobe development; early transient motor stereotypies suggest developmental basal ganglia abnormalities and extend previous findings seen in the childhood of later-onset patients.

Real-time separation of multineuron recordings with a DSP32C signal processor.

We have developed a hardware and software package for real-time discrimination of multiple-unit activities recorded simultaneously from multiple microelectrodes using a VME-Bus system. Compared with other systems cited in literature or commercially available, our system has the following advantages. (1) Each electrode is served by its own preprocessor (DSP32C); (2) On-line spike discrimination is performed independently for each electrode. (3) The VME-bus allows processing of data received from 16 electrodes. The digitized (62.5 kHz) spike form is itself used as the model spike; the algorithm allows for comparing and sorting complete wave forms in real time into 8 different models per electrode.

Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response.

BACKGROUND: Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia. METHOD: Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography. RESULTS: The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects. CONCLUSION: Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.

The topography of tangential inhibitory connections in the postnatally developing and mature striate cortex of the cat.

Clustered intrinsic connections in the striate cortex of kittens originate from an unclustered, diffusely organized pattern prevailing during the first postnatal week. In order to study the participation of inhibitory neurons in this reorganization of the connections, we determined the topography of the inhibitory tangenital connections in the striate cortex of cats ranging in age between 7 and 330 days by combining retrograde transport of fluorescent microspheres with GABA immunohistochemistry. After small intracortical injections of tracer, neurons containing either microspheres only (non-GABAergic neurons) or GABA-like immunoreactivity in addition to microspheres (GABAergic neurons) are labelled at various horizontal distances from the injection. At the end of the first postnatal week, both GABAergic and non-GABAergic neurons are distributed in the horizontal plane in an unclustered fashion. During the second postnatal week, the tangential connections rearrange rapidly to form clusters. The tendency of the cells to form clusters is much weaker, however, in GABAergic than in non-GABAergic neurons. In regions > 500 microns distant from the centre of injection approximately 90% of the non-GABAergic neurons (range 87.5-92.6%) but only 63% (range 57.1-72.3%) of the GABAergic neurons reside within the clusters formed by the non-GABAergic neurons. These proportions do not change systematically with age. In the regions outside the non-GABAergic clusters, GABAergic neurons appear to be evenly distributed and not to aggregate in clusters. From postnatal day 7 forward GABAergic neurons largely retain their overall distribution and density in the horizontal plane. When considering all cortical layers (including the superficial white matter) the lateral spread of the GABAergic neurons is more restricted than that of the non-GABAergic neurons. Systematic changes in the lateral spread of inhibitory connections according to postnatal age were not observed. We conclude that, like the non-GABAergic neurons, the GABAergic neurons have attained an adult-like topography in the horizontal plane by about the end of the second postnatal week. From that time until adulthood they display much weaker clustering, a higher relative occurrence of short axon collaterals and a more restricted lateral distribution than do the excitatory neurons.