‘Born to …’— Genetics and Behaviour

In its ascendancy, the study of human genetics is shifting from the inheritance of physical structure to that of behaviour and personality; seeking the secret machinery which joins the inherited code to the quirk of character. At the start of the century human behaviour was thought to be largely learned and to stem from upbringing, the blank slate of personality being moulded by parents and events. What had been learned could be unlearned and this accorded with the idea of free will expressed in Cassius' claim that ‘the fault, dear Brutus, is not in our stars, but in ourselves, that we are underlings’. Now, at the century's close, the influence of breeding is back in fashion, bringing the implacable effects of genetic determinism and bad blood. The implications for the successes and failings of the ‘normal’ population are far-reaching. In learning disability, many of these ideas are contained in the concept of the ‘behavioural phenotype’.     

‘Thank-you for Saying “No”…’

This case study describes an approach to one individual's non-compliant behaviour, which focuses upon reduction of excessive refusal through change of the caregiver interactional style and acknowledgement of the inherent ‘message value’ of escape and avoidance responses. Positive outcomes include not only increased participation, but also greater personal competence, choice and access to ordinary community facilities, with these gains being maintained at three-month follow up. Implications of the approach are discussed.     

Exercise modifies α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor expression in striatopallidal neurons in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse

The α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic‐acid‐type glutamate receptor (AMPAR) plays a critical role in modulating experience‐dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2‐containing channels in MPTP mice. The purpose of this study was to determine whether exercise‐dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D₂R) or striatonigral (D₁R) medium spiny neuron (MSN) striatal projection pathways. Drd₂‐eGFP‐BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D₂R‐MSNs and D₁R‐MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current–voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2‐lacking AMPARs selectively in striatopallidal D₂R‐MSNs and that exercise reverses this effect in MPTP mice. Exercise‐induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D₂R‐MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience‐dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease. © 2013 Wiley Periodicals, Inc.     

Gating by induced Α–Γ asynchrony in selective attention

Visual selective attention operates through top–down mechanisms of signal enhancement and suppression, mediated by α‐band oscillations. The effects of such top–down signals on local processing in primary visual cortex (V1) remain poorly understood. In this work, we characterize the interplay between large‐scale interactions and local activity changes in V1 that orchestrates selective attention, using Granger‐causality and phase‐amplitude coupling (PAC) analysis of EEG source signals. The task required participants to either attend to or ignore oriented gratings. Results from time‐varying, directed connectivity analysis revealed frequency‐specific effects of attentional selection: bottom–up γ‐band influences from visual areas increased rapidly in response to attended stimuli while distributed top–down α‐band influences originated from parietal cortex in response to ignored stimuli. Importantly, the results revealed a critical interplay between top–down parietal signals and α–γ PAC in visual areas. Parietal α‐band influences disrupted the α–γ coupling in visual cortex, which in turn reduced the amount of γ‐band outflow from visual areas. Our results are a first demonstration of how directed interactions affect cross‐frequency coupling in downstream areas depending on task demands. These findings suggest that parietal cortex realizes selective attention by disrupting cross‐frequency coupling at target regions, which prevents them from propagating task‐irrelevant information.     

Mechanisms of status epilepticus: α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor hypothesis

Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ‐aminobutyric acid type A receptor–mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic receptor (AMPAR)‐mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR‐mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit–containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N‐methyl‐d ‐aspartate receptors 10 minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N‐methyl‐d ‐aspartate receptor antagonist MK‐801 in conjunction with diazepam also terminated seizures that were refractory to MK‐801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit–containing AMPAR plasticity in sustaining seizures of SE.     

Non‐classical mechanism of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor channel block by fluoxetine

Antidepressants have many targets in the central nervous system. A growing body of data demonstrates the influence of antidepressants on glutamatergic neurotransmission. In the present work, we studied the inhibition of native Ca²⁺‐permeable and Ca²⁺‐impermeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca²⁺‐impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC₅₀ value for the inhibition of Ca²⁺‐permeable AMPA receptors in giant striatal interneurons was 43 ± 7 μm . The inhibition of Ca²⁺‐permeable AMPA receptors was voltage dependent, suggesting deep binding in the pore. However, the use dependence of fluoxetine action differed markedly from that of classical AMPA receptor open‐channel blockers. Moreover, fluoxetine did not compete with other channel blockers. In contrast to fluoxetine, its membrane‐impermeant quaternary analog demonstrated all of the features of channel inhibition typical for open‐channel blockers. It is suggested that fluoxetine reaches the binding site through a hydrophobic access pathway. Such a mechanism of block is described for ligands of sodium and calcium channels, but was never found in AMPA receptors. Molecular modeling suggests binding of fluoxetine in the subunit interface; analogous binding was proposed for local anesthetics in closed sodium channels and for benzothiazepines in calcium channels.     

Fustin flavonoid attenuates β‐amyloid (1–42)‐induced learning impairment

Natural flavonoids ameliorate amyloid‐β peptide (Aβ)‐induced neurotoxicity. We examined whether the fustin flavonoid affects Aβ‐induced learning impairment in mice. Repeated treatment with fustin significantly attenuated Aβ (1–42)‐induced conditioned fear and passive avoidance behaviors. This effect was comparable to that of EGb761, a standard extract of ginkgo. Fustin treatment significantly prevented decreases in acetylcholine (ACh) levels, choline acetyltransferase (ChAT) activity, and ChAT gene expression induced by Aβ (1–42). Fustin also consistently suppressed increases in acetyl cholinesterase (AChE) activity and AChE gene expression induced by Aβ (1–42). In addition, fustin significantly attenuated Aβ (1–42)‐induced selective decreases in muscarinic M1 receptor gene expression and muscarinic M1 receptor binding activity (as determined by [³H]pirenzepine binding) by modulating extracellular signal‐regulated kinase 1/2 (ERK 1/2) and cAMP response‐element binding protein (CREB) phosphorylation and brain‐derived neurotrophic factor (BDNF) expression. These effects of fustin were reversed by treatment with dicyclomine, a muscarinic M1 receptor antagonist, and SL327, a selective ERK inhibitor, but not by chelerythrine, a pan‐protein kinase C (PKC) inhibitor. Taken together, our results suggest that fustin attenuates Aβ (1–42)‐impaired learning, and that the ERK/CREB/BDNF pathway is important for the M1 receptor‐mediated cognition‐enhancing effects of fustin. © 2009 Wiley‐Liss, Inc.