Enhanced prefrontal serotonin 5-HT1A currents in a mouse model of Williams-Beuren syndrome with low innate anxiety

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1+/−) or homozygously (Gtf2ird1−/−) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1−/− mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1−/− mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1−/− mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT1A receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT1A receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT1A receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT1A-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1−/− mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines

Impact of Dendritic Size and Dendritic Topology on Burst Firing in Pyramidal Cells

Neurons display a wide range of intrinsic firing patterns. A particularly relevant pattern for neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of action potentials with short interspike intervals. Besides ion-channel composition, dendritic morphology appears to be an important factor modulating firing pattern. However, the underlying mechanisms are poorly understood, and the impact of morphology on burst firing remains insufficiently known. Dendritic morphology is not fixed but can undergo significant changes in many pathological conditions. Using computational models of neocortical pyramidal cells, we here show that not only the total length of the apical dendrite but also the topological structure of its branching pattern markedly influences inter- and intraburst spike intervals and even determines whether or not a cell exhibits burst firing. We found that there is only a range of dendritic sizes that supports burst firing, and that this range is modulated by dendritic topology. Either reducing or enlarging the dendritic tree, or merely modifying its topological structure without changing total dendritic length, can transform a cell's firing pattern from bursting to tonic firing. Interestingly, the results are largely independent of whether the cells are stimulated by current injection at the soma or by synapses distributed over the dendritic tree. By means of a novel measure called mean electrotonic path length, we show that the influence of dendritic morphology on burst firing is attributable to the effect both dendritic size and dendritic topology have, not on somatic input conductance, but on the average spatial extent of the dendritic tree and the spatiotemporal dynamics of the dendritic membrane potential. Our results suggest that alterations in size or topology of pyramidal cell morphology, such as observed in Alzheimer's disease, mental retardation, epilepsy, and chronic stress, could change neuronal burst firing and thus ultimately affect information processing and cognition

Effects of Adrenalectomy on the Excitability of Neurosecretory Parvocellular Neurones in the Hypothalamic Paraventricular Nucleus

Glucocorticoids are well known to inhibit the release of hypophysiotrophic hormones from neurones originating in the paraventricular nucleus (PVN), but the cellular mechanisms of the inhibition are not well understood. Here, we examined the effects of adrenalectomy (ADX) on the spontaneous firing activity in the neurosecretory parvocellular PVN neurones of rat brain slices. The neurones were identified by injecting a retrograde dye into the pituitary stalk and classified according to their electrophysiological properties. The intranuclear distribution, electrophysiological properties, and hypophysiotrophic hormone phenotype of the labelled type II PVN neurones were similar to neurosecretory parvocellular PVN neurones. In the neurones of sham-operated rats under the cell-attached recording mode, we observed three spontaneous activity patterns: tonic regular (24%), tonic irregular (36%), and silent (40%). Noradrenaline (100 µM) induced an excitatory or an inhibitory effect on the spontaneous activity. Noradrenergic excitation was blocked by prazosin (2 µM, α1-adrenoceptor antagonist), and mimicked by phenylephrine (100 µM, α1-adrenoceptor agonist), whereas noradrenergic inhibition was blocked by yohimbine (2 µM, α2-adrenoceptor antagonist) and mimicked by clonidine (50 µM, α2-adrenoceptor agonist). In the neurones of ADX rats, we found burst firing in 35% of neurones tested and an increase in the frequency of spontaneous firing. The burst firing was not observed in the neurones of the sham-operated rats. ADX caused a 1.7-fold increase in the proportion of neurones showing the noradrenergic excitation. Supplementation of the ADX rats with corticosterone (10 mg pellet) reversed the ADX-induced burst firing, and the potentiation of noradrenergic excitation. In summary, our results show that removal of corticosterone by ADX can elevate the neuronal excitability by increasing the spontaneous firing rate and by potentiating the α1-adrenoceptor-mediated noradrenergic excitation, and it can facilitate hormone release by inducing burst firing. Our results provide new insight to the cellular mechanisms of the feedback inhibition by glucocorticoids in the neurosecretory parvocellular neurones of the PVN.The authors wish to thank Dr Quentin Pittman for his indispensable advice and Dr KH Lee for his technical assistance. This work was supported by a grant (R01-2002-000-00128-0) from the Basic Research Programme of the Korea Science & Engineering Foundation

Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus

Serotonin receptor 1A knockout (Htr1a(KO)) mice show increased anxiety-related behavior in tests measuring innate avoidance. Here we demonstrate that Htr1a(KO) mice show enhanced fear conditioning to ambiguous conditioned stimuli, a hallmark of human anxiety. To examine the involvement of specific forebrain circuits in this phenotype, we developed a pharmacogenetic technique for the rapid tissue- and cell type–specific silencing of neural activity in vivo. Inhibition of neurons in the central nucleus of the amygdala suppressed conditioned responses to both ambiguous and nonambiguous cues. In contrast, inhibition of hippocampal dentate gyrus granule cells selectively suppressed conditioned responses to ambiguous cues and reversed the knockout phenotype. These data demonstrate that Htr1a(KO) mice have a bias in the processing of threatening cues that is moderated by hippocampal mossy-fiber circuits, and suggest that the hippocampus is important in the response to ambiguous aversive stimuli