Dynamic regulation of the extracellular matrix in reward memory processes: a question of time

Substance use disorders are a global health problem with increasing prevalence resulting in significant socioeconomic burden and increased mortality. Converging lines of evidence point to a critical role of brain extracellular matrix (ECM) molecules in the pathophysiology of substance use disorders. An increasing number of preclinical studies highlight the ECM as a promising target for development of novel cessation pharmacotherapies. The brain ECM is dynamically regulated during learning and memory processes, thus the time course of ECM alterations in substance use disorders is a critical factor that may impact interpretation of the current studies and development of pharmacological therapies. This review highlights the evidence for the involvement of ECM molecules in reward learning, including drug reward and natural reward such as food, as well as evidence regarding the pathophysiological state of the brain’s ECM in substance use disorders and metabolic disorders. We focus on the information regarding time-course and substance specific changes in ECM molecules and how this information can be leveraged for the development of therapeutic strategies

Growth hormone biases amygdala network activation after fear learning

Prolonged stress exposure is a risk factor for developing posttraumatic stress disorder, a disorder characterized by the ‘over-encoding’ of a traumatic experience. A potential mechanism by which this occurs is through upregulation of growth hormone (GH) in the amygdala. Here we test the hypotheses that GH promotes the over-encoding of fearful memories by increasing the number of neurons activated during memory encoding and biasing the allocation of neuronal activation, one aspect of the process by which neurons compete to encode memories, to favor neurons that have stronger inputs. Viral overexpression of GH in the amygdala increased the number of amygdala cells activated by fear memory formation. GH-overexpressing cells were especially biased to express the immediate early gene c-Fos after fear conditioning, revealing strong autocrine actions of GH in the amygdala. In addition, we observed dramatically enhanced dendritic spine density in GH-overexpressing neurons. These data elucidate a previously unrecognized autocrine role for GH in the regulation of amygdala neuron function and identify specific mechanisms by which chronic stress, by enhancing GH in the amygdala, may predispose an individual to excessive fear memory formation.National Institute of Mental Health (U.S.) (NIMH R01 MH084966)United States. Defense Advanced Research Projects Agency (DARPA grant W911NF-10-1-0059)United States. Army Research Offic

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

Mechanism of inhibition of LTP induction by preconditioning stimulation in the rat dentate gyrus in vitro

THESIS 7203The modulation of synaptic plasticity (LTP) by prior synaptic activity represented by preconditioning stimulation (weak HFS) was investigated in the medial perforant pathway of the dentate gyrus in vitro. The inhibition of LTP by preconditioning stimulation represented by weak HFS has been observed previously in CA1 (Huang et al, 1992). The results reported in this thesis have verified that similar inhibition occurs in the medial perforant path of the dentate gyrus. In addition, a possible model for the mechanism of inhibition of LTP by preconditioning stimulation has been proposed. Previous synaptic activity resulting in a change in the capabilities of synapse to undergo subsequent plasticity has been referred to as metaplasticity

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

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

Decrease of AP frequency in the presence of KA in SO CA2/3 fast-spiking interneurons PICRO–treated rats is partially relieved by the blockade of GABA receptors.

<p><b>A</b>, The GABA_A and GABA_B antagonists picrotoxin and CGP55845, respectively, induced a significant increase of AP frequency compared to recordings with KA only application (PICRO+KA plot here is the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032483#pone-0032483-g001" target="_blank">Figure 1D</a>) (ANOVA: p = 0.05, n = 7) (see red labeled symbol). It also resulted in a decrease in AHP (<b>C</b>). <b>B</b>, Representative traces recorded in slices from PICRO-treated rats (left) with KA (middle) and CGP55845 with picrotoxin (right) in the external solution. **p<0.01. Error bars are SEM.</p

The reduced responsiveness of fast-spiking interneurons from PICRO-treated rats to KA is mediated by GluR6/7 subunit-containing KARs.

<p>The GluR6/7 receptor antagonist (NS102) does not have a significant effect on duration (<b>A</b>), RMP (<b>B</b>), AHP (<b>C</b>) or AP frequency (<b>D, E</b>) in SO CA2/3 fast-spiking interneurons from PICRO- infused rats compared to conditions with no drug application. <b>E</b>, Right side of the panel shows representative traces recorded with and without NS102 in the external solution. <b>F</b>, AP spike frequency after NS102 bath perfusion compared to SAL with KA (the plot showing the SAL with KA data is the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032483#pone-0032483-g001" target="_blank">Figure 1D</a>) (ANOVA: p = 0.0001). *p<0.05 or **p<0.01. Error bars are SEM.</p