Ghrelin is an orexigenic peptide and a growth hormone (GH) secretagogue. Secretory dynamics of ghrelin have not been characterized in adolescents with anorexia nervosa (AN). We hypothesized that, compared with healthy adolescents, girls with AN would have increased ghrelin concentrations measured over 12 h of nocturnal sampling from increased basal and pulsatile secretion, and endogenous ghrelin would independently predict GH and cortisol. We examined ghrelin concentration and secretory dynamics in 22 girls with AN and 18 healthy adolescents 12-18 yr old. Associations between ghrelin, various hormones, and measures of insulin resistance were examined. On Cluster analysis, girls with AN had higher ghrelin concentrations than controls, including total area under the curve (AUC) (P ϭ 0.002), nadir (P ϭ 0.0006), and valley levels (P ϭ 0.002). On deconvolution analysis, secretory burst amplitude (P ϭ 0.03) and burst mass (P ϭ 0.04) were higher in AN, resulting in higher pulsatile (P ϭ 0.05) and total ghrelin secretion (P ϭ 0.03). Fasting ghrelin independently predicted GH burst frequency (r ϭ 0.44, P ϭ 0.005). The nutritional markers body mass index and body fat predicted postglucose and valley ghrelin but not fasting levels. Ghrelin parameters were inversely associated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and IGF-I. HOMA-IR was the most significant predictor of most ghrelin parameters. Valley ghrelin independently predicted cortisol burst frequency (52% of variability), and ghrelin parameters independently predicted total triiodothyronine and LH levels. Higher ghrelin concentrations in adolescents with AN are a consequence of increased secretory burst mass and amplitude. The most important predictor of ghrelin concentration is insulin resistance, and ghrelin in turn predicts GH and cortisol burst frequency. growth hormone; cortisol; total triiodothyronine; estradiol; luteinizing hormone; insulin resistance GHRELIN, A 28-AMINO ACID PEPTIDE, is a growth hormone (GH) secretagogue (2, 4, 25, 26, 50 -53) that is also orexigenic (40,56). It is unknown whether elevated ghrelin values are an important contributing factor to the elevated GH levels that occur in anorexia nervosa (AN), a unique model of chronic undernutrition. We have demonstrated higher fasting ghrelin levels in adolescent girls with AN compared with healthy adolescents and higher nadir ghrelin levels following an oral glucose load (36). Girls with AN also have higher GH concentrations, a consequence of increased basal GH secretion and secretory burst frequency (33). Similarly, elevated ghrelin (21, 39) and GH concentrations (47, 49) have been reported in adult women with AN. Negative feedback from low IGF-I levels has been hypothesized to cause increased GH secretion, and the relationship between ghrelin and GH secretion in AN has not been explored.Administration of a single dose of intravenous ghrelin causes an increase in GH secretion in both rodent models (51, 66) and healthy adults (4, 50, 52). Howe...

Leptin, an adipocytokine that suppresses appetite and may regulate neuroendocrine pathways, is low in undernourished states like anorexia nervosa (AN). Although leptin exhibits pulsatility, secretory characteristics have not been well described in adolescents and in AN, and the contribution of hypoleptinemia to increased growth hormone (GH) and cortisol in AN has not been explored. We hypothesized that hypoleptinemia in AN reflects decreased basal and pulsatile secretion and may predict increased GH and cortisol levels. Sampling for leptin, GH, cortisol, and ghrelin was performed every 30 min (from 2000 to 0800) in 23 AN and 21 controls 12-18 yr old, and data were analyzed using Cluster and deconvolution methods. Estradiol, thyroid hormones, and body composition were measured. AN girls had lower pulsatile and total leptin secretion than controls (P < 0.0001) subsequent to decreased burst mass (P < 0.0001) and basal secretion (P = 0.02). Nutritional markers predicted leptin characteristics. In a regression model including BMI, body fat, and ghrelin, leptin independently predicted GH burst interval and frequency. Valley leptin contributed to 56% of the variability in GH burst interval, and basal leptin and fasting ghrelin contributed to 42% of variability in burst frequency. Pulsatile leptin independently predicted urine free cortisol/creatinine (15% of variability). Valley leptin predicted cortisol half-life (22% of variability). Leptin predicted estradiol and thyroid hormone levels. In conclusion, hypoleptinemia in AN is subsequent to decreased basal and pulsatile secretion and nutritionally regulated. Leptin predicts GH and cortisol parameters and with ghrelin predicts GH burst frequency. Low leptin and high ghrelin may be dual stimuli for high GH concentrations in undernutrition.

Ghrelin secretion predicts bone density independent of body composition, the GH-IGF-I axis, cortisol, or estradiol in healthy girls but not in those with AN.

Persistent anion conductances through GABA A receptors (GABA A R) are important modulators of neuronal excitability. However, it is currently unknown how the amplitudes of these currents vary amongst different cell types in the human neocortex, particularly amongst diverse GABAergic interneurons. We have recorded 101 interneurons in and near layer 1 from cortical tissue surgically resected from both male and female patients, visualised 84 of them and measured tonic GABA A R currents in 48 cells with an intracellular [Cl -] of 65 mM and in the presence of 5 µM GABA. We compare these tonic currents amongst five groups of interneurons divided by firing properties and four types of interneuron defined by axonal distributions; rosehip, neurogliaform, stalked-bouton, layers 2-3 innervating and a pool of other cells. Interestingly, the rosehip cell, a type of interneuron only described thus far in human tissue, and layers 2-3 innervating cells exhibit larger tonic currents than other layer 1 interneurons, such as neurogliaform and stalked-bouton cells; the latter two groups showing no difference. The positive allosteric modulators of GABA A Rs allopregnanolone and DS2 also induced larger current shifts in the rosehip and layer 2-3 innervating cells, consistent with higher expression of the δ-subunit of the GABA A R in these neurons. We have also examined how patient parameters, such as age, seizures, type of cancer and anticonvulsant treatment may alter tonic inhibitory currents in human neurons.The cell type specific differences in tonic inhibitory currents could potentially be used to selectively modulate cortical circuitry. Significance statementTonic currents through GABA A receptors are a potential therapeutic target for a number of neurological and psychiatric conditions. Here we show that these currents in human cerebral cortical GABAergic neurons display cell-type specific differences in their amplitudes 4 which implies differential modulation of their excitability. Additionally, we examine whether the amplitudes of the tonic currents measured in our study show any differences between patient populations, finding some evidence that age, seizures, type of cancer, and anticonvulsant treatment may alter tonic inhibition in human tissue. These results advance our understanding of how pathology affects neuronal excitability and could potentially be used to selectively modulate cortical circuitry.

Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar “horsetail” axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline), but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialised, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.