Kainate Receptor-Mediated Modulation of Hippocampal Fast Spiking Interneurons in a Rat Model of Schizophrenia

Kainate receptor (KAR) subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP) in schizophrenia (SZ) and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO) of sectors CA2/3, where the basolateral amygdala (BLA) sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP) amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in response to amygdala activation may lead to abnormal oscillatory rhythms reported in SZ subjects

Functional magnetic resonance imaging (fMRI) of attention processes in presumed obligate carriers of schizophrenia: preliminary findings

<p>Abstract</p> <p>Background</p> <p>Presumed obligate carriers (POCs) are the first-degree relatives of people with schizophrenia who, although do not exhibit the disorder, are in direct lineage of it. Thus, this subpopulation of first-degree relatives could provide very important information with regard to the investigation of endophenotypes for schizophrenia that could clarify the often contradictory findings in schizophrenia high-risk populations. To date, despite the extant literature on schizophrenia endophenotypes, we are only aware of one other study that examined the neural mechanisms that underlie cognitive abnormalities in this group. The aim of this study was to investigate whether a more homogeneous group of relatives, such as POCs, have neural abnormalities that may be related to schizophrenia.</p> <p>Methods</p> <p>We used functional magnetic resonance imaging (fMRI) to collect blood oxygenated level dependent (BOLD) response data in six POCs and eight unrelated healthy controls while performing under conditions of sustained, selective and divided attention.</p> <p>Results</p> <p>The POCs indicated alterations in a widely distributed network of regions involved in attention processes, such as the prefrontal and temporal (including the parahippocampal gyrus) cortices, in addition to the anterior cingulate gyrus. More specifically, a general reduction in BOLD response was found in these areas compared to the healthy participants during attention processes.</p> <p>Conclusion</p> <p>These preliminary findings of decreased activity in POCs indicate that this more homogeneous population of unaffected relatives share similar neural abnormalities with people with schizophrenia, suggesting that reduced BOLD activity in the attention network may be an intermediate marker for schizophrenia.</p

NMDA and Dopamine Converge on the NMDA-Receptor to Induce ERK Activation and Synaptic Depression in Mature Hippocampus

The formation of enduring internal representation of sensory information demands, in many cases, convergence in time and space of two different stimuli. The first conveys the sensory input, mediated via fast neurotransmission. The second conveys the meaning of the input, hypothesized to be mediated via slow neurotransmission. We tested the biochemical conditions and feasibility for fast (NMDA) and slow (dopamine) neurotransmission to converge on the Mitogen Activated Protein Kinase signaling pathways, crucial in several forms of synaptic plasticity, and recorded its effects upon synaptic transmission. We detected differing kinetics of ERK2 activation and synaptic strength changes in the CA1 for low and high doses of neurotransmitters in hippocampal slices. Moreover, when weak fast and slow inputs are given together, they converge on ERK2, but not on p38 or JNK, and induce strong short-term synaptic depression. Surprisingly, pharmacological analysis revealed that a probable site of such convergence is the NMDA receptor itself, suggesting it serves as a detector and integrator of fast and slow neurotransmission in the mature mammalian brain, as revealed by ERK2 activation and synaptic function

AP firing rate is decreased while AHP is increased in SO of CA2/3 fast–spiking interneurons of PICRO-treated rats in the presence of kainic acid (KA).

<p>Application of KA does not affect duration (<b>A</b>) or RMP (<b>B</b>) in PICRO-treated rats compared to experimental conditions with no drug. In contrast, AHP is increased (<b>C</b>) and AP firing rate is decreased in PICRO rats compared with saline–infused animals in the presence of KA (<b>D, E</b>). Insets in <b>C</b>, <b>E</b> show representative traces of interneuron AP responses from SAL (on the left) and PICRO (on the right) infused animals. <b>F</b>, Plot of instantaneous firing frequency versus time for spikes elicited by single current steps during the first 500 ms of a 1s current pulse in slices from PICRO rats with or without KA in the external solution. * p = <0.05 or ***p<0.001. Error bars indicate SEM.</p

A schematic diagram depicting how an increase of excitatory activity from the BLA might influence the interaction of inhibitory and disinhibitory GABA cells in the SO of CA2/3.

<p>The results reported in this study can be best explained by a model in which BLA afferents influence two types of interneurons: one that is a fast–spiking (FS) inhibitory cell (red) and one that is a disinhibitory neuron (green) that forms GABA-to-GABA interactions with the FS interneuron (<b>1</b>). The diagram suggests that BLA fibers may provide two different KARs-mediated glutamatergic interactions with the disinhibitory neuron. Because PICRO-infused rats showed a significant increase in the amplitude of AHPs in FS-cells, these glutamatergic fibers probably stimulate the KARs located in dendrites of disinhibitory neuron through axodendritic connections (<b>2</b>). Additionally, the further increase in the amplitude of AHPs recorded in FS cells observed in PICRO-treated rats with blockade of the GluR5 subunits of KARs suggests that BLA fibers may also provide a pre-synaptic inhibitory effect of the dysinhibitory axon terminal synapting on the FS cells. This last effect is mediated by GluR5 or 6/7 on GABA-to-GABA terminals (<b>3</b>). BLA fibers have been found to form axo-axonic connections in cortical neuropil (Cunningham et al. 2002) and, in the SO of CA2/3, similar connections with the axon terminations of disinhibitory interneurons maybe present. This circuitry model provides new insights as to how BLA fibers may contribute to the synchronization of oscillatory rhythms generated in the amygdala and hippocampus during normal and abnormal cognitive states.</p

Community use of face masks against the spread of covid-19

The role of face masks to prevent and control COVID-19 is critical, especially since asymptomatic or pre-symptomatic infected individuals can shed high loads of SARS-CoV-2 in the surrounding environment. In addition to being a two-way barrier to protect against virions droplets both in terms of “source control” (for the benefits of the community) and “physical protection” (for wearer), face masks also allow maintaining physiological temperatures and humidity of the nasal cavity and mouth, independently from the external environmental conditions. Beyond compromising the viral transmission speed, exposure to cold environments could have a detrimental effect on the host’s susceptibility to SARS-CoV-2. The innate human immune system becomes in fact weaker with cooler nose temperatures and thus more vulnerable to viral replication. Furthermore, there is evidence that warm, humid climates are associated with reduced spread of SARS-CoV-2, while cold dry conditions favor its stability and transmissibility. In the early stage of a viral infection, a physiological body temperature in the upper airways supports the innate immune system, endorsing the muco-ciliary clearance, inhibiting, or deactivating any first settlement of viruses. Face masks are therefore strongly recommended also outdoors, especially under cold weather conditions, not only as a physical barrier against the transmission of SARS-CoV-2, but also to prevent the rapid cooling of the nasal mucosa and the inhibition of the human innate defense of the upper airways

ZD7288 reverses the increase of AP frequency induced by CGP55845 with picrotoxin in SO CA2/3 fast-spiking interneurons PICRO–treated rats.

<p><b>A</b>, <b>B</b>, Application of the Ih blocker ZD7288 significantly decreases AP frequency and increases duration (<b>C</b>) compared to recordings with CGP55845 (GABA_B antagonist) and picrotoxin (GABA_A antagonist) (the red labeled plot is the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032483#pone-0032483-g004" target="_blank">Figure 4E</a>) bath application (ANOVA: p = 0.02, n = 6). In contrast, bath perfusion of tertiapin-Q did not have a significant effect on interneuronal electrophysiological properties (<b>A</b>, <b>B</b>, <b>C</b>). Traces on the bottom of the panel were recorded with the application of KA and GABA_A,B blockers (left), tertiapin-Q- (middle) and ZD7288 (right). ***p<0.001. Error bars are SEM.</p

I/R values of SO-CA2/3 FS-Interneurons in SAL and PICRO- Treated Rats.

<p>See Methods sections for details.</p><p>SAL, saline; PICRO, picrotoxin; SO, stratum oriens; I/R, input resistance;</p>a<p>p = 0.015.</p>b<p>p = 0.001.</p