За кадры. 1988. № 47 (2773)

7 октября - День конституции СССРКаким быть парткому? / Э. Н. КамышевПартгрупоргНаш многонациональный дом / Г. В. ЯловскаяПервые вожаки комсомола / Е. ПершинаНа закладке овощейЧто за тонной и гектаром? / А. ЯковлевБыстрое чтениеОсенний десант в Чаинск / В. ЯнковскийРаботают рядомСуметь понять другогоТак держать! / Т. ПоляковаНужны энтузиасты / Д. МайоровНакануне новоселья / А. ТаенковНе смешно! / В. Краснокутски

Novel Environment and GABA Agonists Alter Event-Related Potentials in N-Methyl-d-aspartate NR1 Hypomorphic and Wild-Type Mice

Clinical and experimental data suggest dysregulation of N-methyl-d-aspartate receptor (NMDAR)-mediated glutamatergic pathways in schizophrenia. The interaction between NMDAR-mediated abnormalities and the response to novel environment has not been studied. Mice expressing 5 to 10% of normal N-methyl-d-aspartate receptor subunit 1 (NR1) subunits [NR1neo(−/−)] were compared with wild-type littermates for positive deflection at 20 ms (P20) and negative deflection at 40 ms (N40) auditory event-related potentials (ERPs). Groups were tested for habituation within and across five testing sessions, with novel environment tested during a sixth session. Subsequently, we examined the effects of a GABAA positive allosteric modulator (chlordiazepoxide) and a GABAB receptor agonist (baclofen) as potential interventions to normalize aberrant responses. There was a reduction in P20, but not N40 amplitude within each habituation day. Although there was no amplitude or gating change across habituation days, there was a reduction in P20 and N40 amplitude and gating in the novel environment. There was no difference between genotypes for N40. Only NR1neo(−/−) mice had reduced P20 in the novel environment. Chlordiazepoxide increased N40 amplitude in wild-type mice, whereas baclofen increased P20 amplitude in NR1neo(−/−) mice. As noted in previous publications, the pattern of ERPs in NR1neo(−/−) mice does not recapitulate abnormalities in schizophrenia. In addition, reduced NR1 expression does not influence N40 habituation but does affect P20 in a novel environment. Thus, the pattern of P50 (positive deflection at 50 ms) but not N100 (negative deflection at 100 ms) in human studies may relate to subjects’ reactions to unfamiliar environments. In addition, NR1 reduction decreased GABAA receptor-mediated effects on ERPs while causing increased GABAB receptor-mediated effects. Future studies will examine changes in GABA receptor subunits after reductions in NR1 expression

Nicotine receptor subtype-specific effects on auditory evoked oscillations and potentials.

Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity.We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma.These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2 receptors. Event-related gamma is strongly influenced by activation of α4β2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes

Nicotine receptor subtype-specific effects on auditory evoked gamma oscillations.

<p>(Top) Event-related Gamma (30 to 80 Hz) activity following nicotine and nicotine receptor antagonists. Assessment of the effects of nicotine antagonists was carried out using a within subjects design in which each mouse was assessed on each drug, with sessions being separated by a 24 hour washout period. N = 13 for each condition. Depicted top left <b>A</b>) is the average event-related gamma power (in dB) for the period between 0 and 60 msec following stimulus onset, across all 50 stimulus presentations. This was done by calculating the time-frequency response for each wavelet cycle within the 0 to 60 msec period and averaging the resulting values to create a single number. All statistical analyses were conducted on these values. Nicotine (1 mg/kg) caused an increase in evoked gamma activity, which was blocked by DHβE (2 mg/kg) but not MLA (10 mg/kg), indicating that the positive effect of nicotine on gamma activity is mediated through the α4β2 receptor subtype. # indicates p<0.05. Top center <b>B</b>) depicts event-related gamma power across each individual wavelet cycle between 100 msec pre-stimulus and 200 msec post-stimulus across all 50 stimulus presentations. Depicted top left <b>C</b>) is a heat map showing event-related power in decibels (event-related spectral perturbation, i.e. the power following the stimulus expressed as a change from baseline) from 200 msec prior to stimulus onset to 200 msec post onset (0 = stimulus onset) across all 50 stimulus presentations following vehicle and nicotine treatment. (Bottom) Event-related Gamma activity following administration of the α4β2 specific agonist AZD3480. Assessment of the effects of AZD3480 was carried out using a within subjects design in which each mouse was assessed on each drug, with sessions being separated by a 72 hour washout period. The mice used to assess AZD3480 were a separate cohort from those shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039775#pone-0039775-g002" target="_blank">Figure 2A</a> used to assess nicotine antagonists. N = 9 for each condition. Bottom left D) shows a significant increase in event-related gamma following low (1 mg/kg), but not high (10 mg/kg) dose AZD3480. The methodology used to create bottom left <b>D</b>), center <b>E</b>) and right <b>F</b>) figures are the same used to create figures <b>A</b>, <b>B</b> and <b>C</b>, respectively. # - indicates significant differences from saline vehicle (all p<0.05).</p