Search

The prefrontal cortex (PFC) plays an important role in social behavior and is sensitive to stressful circumstances. Challenging life conditions might change PFC function and put individuals at risk for maladaptive social behavior. The excitation-inhibition (EI) balance of prefrontal neurons appears to play a crucial role in this process. Here, we examined how a challenging life condition in C57BL/6JolaHsd mice, i.e. group-housing 6 mice in a complex environment for 10 days in adulthood, changes the EI-balance of infralimbic prefrontal neurons in layer 2/3, compared to standard pair-housing. Slices were prepared from "undisturbed" mice, i.e. the first mouse taken from the cage, or mice taken ∼15 min later, who were mildly aroused after removal of the first mouse. We observed a housing-condition by arousal-state interaction, with in the complex housing group an elevated EI-balance in undisturbed and reduced EI-balance in mildly aroused animals, while no differences were observed in standard housed animals. The change was explained by a shift in mIPSC and mEPSC frequency, while amplitudes remained unaffected. Female mice showed no housing-by-state interaction, but a main effect of housing was found for mIPSCs, with a higher frequency in complex- versus standard-housed females. No effects were observed in males who were complex-housed from a young age onwards. Explorative investigations support a potential mediating role of corticosterone in housing effects on the EI-balance of males. We argue that taking the arousal state of individuals into account is necessary to better understand the consequences of exposure to challenging life conditions for prefrontal function. • Individual differences to thrive might be highly dependent on past social experiences. • PFC electrophysiology was changed in male mice after complex housing in adulthood. • This change was affected by acute arousal state and not observed in females. • Corticosterone might mediate the housing effects on PFC excitation and inhibition. [ABSTRACT FROM AUTHOR]

The striatum can be divided into the DLS (dorsolateral striatum) and the VMS (ventromedial striatum), which includes NAcC (nucleus accumbens core) and NAcS (nucleus accumbens shell). Here, we examined differences in electrophysiological properties of MSSNs (medium-sized spiny neurons) based on their location, expression of DA (dopamine) D1/D2 receptors and responses to the μ-opioid receptor agonist, DAMGO {[D-Ala(2)-MePhe(4)-Gly(ol)(5)]enkephalin}. The main differences in morphological and biophysical membrane properties occurred among striatal sub-regions. MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS. RMPs (resting membrane potentials) were similar among regions except for D2 cells in the NAcC, which displayed a significantly more depolarized RMP. In contrast, differences in frequency of spontaneous excitatory synaptic inputs were more prominent between cell types, with D2 cells receiving significantly more excitatory inputs than D1 cells, particularly in the VMS. Inhibitory inputs were not different between D1 and D2 cells. However, MSSNs in the VMS received more inhibitory inputs than those in the DLS. Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount. DAMGO also increased cellular excitability in the VMS, as shown by reduced threshold for evoking APs (action potentials). Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

Early-onset drinking during childhood or preadolescence is a serious social problem. Yet, most of the basic neurobiological research on the acute effects of ethanol has been carried out on adult or early postnatal animals. We studied the effect of alcohol exposure on the basic electrophysiological properties and cell viability of layer 5 pyramidal neurons from the somatosensory cortex of juvenile (P21-P23) C57BL/6N mice. After bath application of 50 mM ethanol to acute slices of the somatosensory cortex, no adverse effects were detected on cells survival, whereas the input resistance and firing rate of layer 5 neurons were significantly reduced. While the effect on the input resistance was reversible, the depressing effect on cell firing remained stable after 6 min of alcohol exposure. Ethanol application did not result in any significant change of mIPSC frequency, amplitude, and rise time. A slight increase of mIPSC decay time was observed after 6 min of ethanol exposure. The molecular mechanisms leading to these alterations and their significance for the physiology of the cerebral cortex are briefly discussed. [ABSTRACT FROM AUTHOR]

Background and Purpose: Benzodiazepines (BDZs) are widely used in clinical practice and are known as positive modulators of GABAergic currents. BDZs increase binding affinity and recently they were found to affect GABA(A) receptor gating, including desensitization. Binding and desensitization are also strongly modulated by extracellular pH, a factor that may be severely altered in a pathological brain. It is thus of interest to examine the combined action of BDZ and protons.Experimental Approach: Pharmacokinetic analysis was based on patch clamp recordings of miniature IPSCs (mIPSCs) and current responses to GABA applications in rat cultured hippocampal neurons. High temporal resolution of currents evoked by exogenous GABA was achieved by using an ultrafast perfusion system (exchange time ca. 80 micros).Key Results: At acidic pH, flurazepam produced a stronger enhancement of mIPSC amplitudes than at physiological pH. At low GABA concentrations, flurazepam markedly enhanced current amplitudes both at normal and acidic pH, but at the latter, the relative effect was larger. In contrast, at saturating GABA concentrations, flurazepam reduced current amplitudes at both pH 7.2 and 6.0. The slowing of deactivation kinetics by flurazepam decreased with GABA concentration, but at pH 6.0, this trend was shifted toward a higher GABA concentration.Conclusions and Implications: Acidification of extracellular medium may significantly affect the susceptibility of phasic and tonic components of GABAergic currents to modulation by BDZs. Quantitative analysis and model simulations indicate that protons and flurazepam additively affect binding and desensitization of GABA(A) receptors. [ABSTRACT FROM AUTHOR]

Miniature GABAA receptor-mediated inhibitory postsynaptic currents (mIPSCs) in cortical pyramidal neurons have previously been categorized into two types: small amplitude mIPSCs with a mono-exponential deactivation (mono-mIPSCs) and relatively larger mIPSCs with bi-exponential deactivation (bi-mIPSCs). The aim of this study was to determine if the GABAA channels that underlie these mIPSCSs are molecularly distinct. We found, using non-stationary noise analysis, that the difference in their amplitude could be not accounted for by their single channel conductance (both were 40 pS). Next, using α subunit selective GABAA receptor modulators, we examined the identity of the α subunits that may be expressed in the synapses that give rise to these mIPSCs. Zolpidem (100 and 500 nm, α1 selective) affected the deactivation of a subset of the mono-mIPSCs, indicating that α1 subunits are not highly expressed in these synapses. However, zolpidem (100 nm) prolonged the deactivation of all bi-mIPSCs, indicating a high abundance of α1 subunits in these synapses. SB-205384 (α3 selective) had no effect on the mono-mIPSCs but the bi-mIPSCs were prolonged. Furosemide (α4 selective) reduced the amplitude of only the mono-mIPSCs. L655,708 (α5 selective) reduced the amplitude of both populations and shortened the duration of the mono-mIPSCs. Finally, we found that the neuroactive steroid pregesterone sulphate reduced the amplitude of both mIPSC types. These results provide pharmacological evidence that synapses on cortical pyramidal neurons are molecularly distinct. The purpose of these different types of synapses may be to provide different inhibitory timing patterns on these cells. [ABSTRACT FROM AUTHOR]

An interaction with the GABA type A (GABAA) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) are, in fact, potent and efficacious endogenous positive modulators of GABAA receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABAA receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3α,5α-THP as well as the amplitude of GABAA receptor-mediated IPSCs recorded from CA1 pyramidal neurons in isolated hippocampal slices. These effects are shared by the neurosteroid precursor progesterone, the peripheral benzodiazepine receptor-selective agonist CB34, and γ-hydroxybutyrate, all of which are known to increase the formation of neuroactive steroids in plasma and in the brain. The action of ethanol on GABAA receptor-mediated IPSC amplitude is biphasic, consisting of a rapid, direct effect on GABAA receptor activity and an indirect effect that appears to be mediated by neurosteroid synthesis. Furthermore, ethanol affects GABAA receptor activity through a presynaptic action, an effect that is not dependent on neurosteroid formation. These observations suggest that ethanol may modulate GABAA receptor function through an increase in de novo neurosteroid synthesis in the brain that is independent of the HPA axis. This novel mechanism may have a crucial role in m. [ABSTRACT FROM AUTHOR]