Epigenetic function during heroin self-administration controls future relapse-associated behavior in a cell type-specific manner.

Opioid use produces enduring associations between drug reinforcement/euphoria and discreet or diffuse cues in the drug-taking environment. These powerful associations can trigger relapse in individuals recovering from opioid use disorder (OUD). Here, we sought to determine whether the epigenetic enzyme, histone deacetylase 5 (HDAC5), regulates relapse-associated behavior in an animal model of OUD. We examined the effects of nucleus accumbens (NAc) HDAC5 on both heroin- and sucrose-seeking behaviors using operant self-administration paradigms. We utilized cre-dependent viral-mediated approaches to investigate the cell-type-specific effects of HDAC5 on heroin-seeking behavior, gene expression, and medium spiny neuron (MSN) cell and synaptic physiology. We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future relapse-associated behavior. Moreover, overexpressing HDAC5 in the NAc suppressed context-associated and reinstated heroin-seeking behaviors, but it did not alter sucrose seeking. We also found that HDAC5 functions within dopamine D1 receptor-expressing MSNs to suppress cue-induced heroin seeking, and within dopamine D2 receptor-expressing MSNs to suppress drug-primed heroin seeking. Assessing cell-type-specific transcriptomics, we found that HDAC5 reduced expression of multiple ion transport genes in both D1- and D2-MSNs. Consistent with this observation, HDAC5 also produced firing rate depression in both MSN classes. These findings revealed roles for HDAC5 during active heroin use in both D1- and D2-MSNs to limit distinct triggers of drug-seeking behavior. Together, our results suggest that HDAC5 might limit relapse vulnerability through regulation of ion channel gene expression and suppression of MSN firing rates during active heroin use.

Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning.

Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 µM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia.

Sex differences in behavior, cognitive, and physiological recovery following methamphetamine administration.

Intact executive functions are required for proper performance of cognitive tasks and relies on balance of excitatory and inhibitory (E/I) transmission in the medial prefrontal cortex (mPFC). Hypofrontality is a state of decreased activity in the mPFC and is seen in several neuropsychiatric conditions, including substance use disorders. People who chronically use methamphetamine (meth) develop hypofrontality and concurrent changes in cognitive processing across several domains. Despite the fact that there are sex difference in substance use disorders, few studies have considered sex as a biological variable regarding meth-mediated hypoactivity in mPFC and concurrent cognitive deficits. Hypofrontality along with changes in cognition are emulated in rodent models following repeated meth administration. Here, we used a meth sensitization regimen to study sex differences in a Temporal Order Memory (TOM) task following short (7 days) or prolonged (28 days) periods of abstinence. GABAergic transmission, GABAA receptor (GABAAR) and GABA Transporter (GAT) mRNA expression in the mPFC were evaluated with patch-clamp recordings and RT-qPCR, respectively. Both sexes sensitized to the locomotor activating effects of meth, with the effect persisting in females. After short abstinence, males and females had impaired TOM and increased GABAergic transmission. Female rats recovered from these changes after prolonged abstinence, whereas male rats showed enduring changes. In general, meth appears to elicit an overall decrease in GABAAR expression after short abstinence; whereas GABA transporters are decreased in meth female rats after prolonged abstinence. These results show sex differences in the long-term effects of repeated meth exposure and suggest that females have neuroprotective mechanisms that alleviate some of the meth-mediated cognitive deficits.

Empirical mode decomposition of local field potential data from optogenetic experiments.

Introduction: This study investigated the effects of cocaine administration and parvalbumin-type interneuron stimulation on local field potentials (LFPs) recorded in vivo from the medial prefrontal cortex (mPFC) of six mice using optogenetic tools. Methods: The local network was subject to a brief 10 ms laser pulse, and the response was recorded for 2 s over 100 trials for each of the six subjects who showed stable coupling between the mPFC and the optrode. Due to the strong non-stationary and nonlinearity of the LFP, we used the adaptive, data-driven, Empirical Mode Decomposition (EMD) method to decompose the signal into orthogonal Intrinsic Mode Functions (IMFs). Results: Through trial and error, we found that seven is the optimum number of orthogonal IMFs that overlaps with known frequency bands of brain activity. We found that the Index of Orthogonality (IO) of IMF amplitudes was close to zero. The Index of Energy Conservation (IEC) for each decomposition was close to unity, as expected for orthogonal decompositions. We found that the power density distribution vs. frequency follows a power law with an average scaling exponent of ~1.4 over the entire range of IMF frequencies 2-2,000 Hz. Discussion: The scaling exponent is slightly smaller for cocaine than the control, suggesting that neural activity avalanches under cocaine have longer life spans and sizes.

Repeated methamphetamine administration produces cognitive deficits through augmentation of GABAergic synaptic transmission in the prefrontal cortex.

Methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. Using PV-Cre transgenic rats that went through a METH sensitization regime or saline (SAL) followed by 7-10 days of home cage abstinence combined with cognitive tests, chemogenetic experiments, and whole-cell patch recordings on the prelimbic prefrontal cortex (PFC), we investigated the cellular and synaptic mechanisms underlying METH-induce hypofrontality. We report here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the PFC. The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, repeated METH administration increases the intrinsic excitability of parvalbumin-positive fast spiking interneurons (PV + FSIs), a key local interneuron population in PFC that contributes to the control of inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV + FSIs activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. Conversely, reducing PV + FSIs activity in the PFC of METH-exposed rats rescues METH-induced temporal order memory deficits. Together, our findings reveal that repeated METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV + FSIs activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from METH use disorder.

Dopamine receptor antagonists effects on low-dimensional attractors of local field potentials in optogenetic mice.

The goal of this study was to investigate the effects of acute cocaine injection or dopamine (DA) receptor antagonists on the medial prefrontal cortex (mPFC) gamma oscillations and their relationship to short term neuroadaptation that may mediate addiction. For this purpose, optogenetically evoked local field potentials (LFPs) in response to a brief 10 ms laser light pulse were recorded from 17 mice. D1-like receptor antagonist SCH 23390 or D2-like receptor antagonist sulpiride, or both, were administered either before or after cocaine. A Euclidian distance-based dendrogram classifier separated the 100 trials for each animal in disjoint clusters. When baseline and DA receptor antagonists trials were combined in a single trial, a minimum of 20% overlap occurred in some dendrogram clusters, which suggests a possible common, invariant, dynamic mechanism shared by both baseline and DA receptor antagonists data. The delay-embedding method of neural activity reconstruction was performed using the correlation time and mutual information to determine the lag/correlation time of LFPs and false nearest neighbors to determine the embedding dimension. We found that DA receptor antagonists applied before cocaine cancels out the effect of cocaine and leaves the lag time distributions at baseline values. On the other hand, cocaine applied after DA receptor antagonists shifts the lag time distributions to longer durations, i.e. increase the correlation time of LFPs. Fourier analysis showed that a reasonable accurate decomposition of the LFP data can be obtained with a relatively small (less than ten) Fourier coefficients.

Methamphetamine Self-Administration Elicits Sex-Related Changes in Postsynaptic Glutamate Transmission in the Prefrontal Cortex.

Preclinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge, we recorded from the prelimbic area of the prefrontal cortex (PL-PFC) of male and female rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during SA; however, female rats exhibit significant synaptic baseline differences when compared to males. Furthermore, females exhibited a significant increase in evoked excitatory currents. This increase in evoked glutamate was correlated with increases in NMDA currents and was not affected by application of a GluN2B selective blocker. We propose that METH SA selectively upregulates GluN2B-lacking NMDA receptors (NMDAR) in the PFC of female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females.

Cocaine-Induced Changes in Low-Dimensional Attractors of Local Field Potentials in Optogenetic Mice.

Optogenetically evoked local field potential (LFP) recorded from the medial prefrontal cortex (mPFC) of mice during basal conditions and following a systemic cocaine administration were analyzed. Blue light stimuli were delivered to mPFC through a fiber optic every 2 s and each trial was repeated 100 times. As in the previous study, we used a surrogate data method to check that nonlinearity was present in the experimental LFPs and only used the last 1.5 s of steady activity to measure the LFPs phase resetting induced by the brief 10 ms light stimulus. We found that the steady dynamics of the mPFC in response to light stimuli could be reconstructed in a three-dimensional phase space with topologically similar "8"-shaped attractors across different animals. Therefore, cocaine did not change the complexity of the recorded nonlinear data compared to the control case. The phase space of the reconstructed attractor is determined by the LFP time series and its temporally shifted versions by a multiple of some lag time. We also compared the change in the attractor shape between cocaine-injected and control using (1) dendrogram clustering and (2) Frechet distance. We found about 20% overlap between control and cocaine trials when classified using dendrogram method, which suggest that it may be possible to describe mathematically both data sets with the same model and slightly different model parameters. We also found that the lag times are about three times shorter for cocaine trials compared to control. As a result, although the phase space trajectories for control and cocaine may look similar, their dynamics is significantly different.

Long-term neuroadaptations produced by withdrawal from repeated cocaine treatment: role of dopaminergic receptors in modulating cortical excitability.

Dopamine (DA) modulates neuronal activity in the prefrontal cortex (PFC) and is necessary for optimal cognitive function. Dopamine transmission in the PFC is also important for the behavioral adaptations produced by repeated exposure to cocaine. Therefore, we investigated the effects of repeated cocaine treatment followed by withdrawal (2-4 weeks) on the responsivity of cortical cells to electrical stimulation of the ventral tegmental area (VTA) and to systemic administration of DA D1 or D2 receptor antagonists. Cortical cells in cocaine- and saline-treated animals exhibited a similar decrease in excitability after the administration of D1 receptor antagonists. In contrast, cortical neurons from cocaine-treated rats exhibited a lack of D2-mediated regulation relative to saline rats. Furthermore, in contrast to saline-treated animals, VTA stimulation did not increase cortical excitability in the cocaine group. These data suggest that withdrawal from repeated cocaine administration elicits some long-term neuroadaptations in the PFC, including (1) reduced D2-mediated regulation of cortical excitability, (2) reduced responsivity of cortical cells to phasic increases in DA, and (3) a trend toward an overall decrease in excitability of PFC neurons.

The ability of the mesocortical dopamine system to operate in distinct temporal modes.

BACKGROUND: This review discusses evidence that cells in the mesocortical dopamine (DA) system influence information processing in target areas across three distinct temporal domains. DISCUSSIONS: Phasic bursting of midbrain DA neurons may provide temporally precise information about the mismatch between expected and actual rewards (prediction errors) that has been hypothesized to serve as a learning signal in efferent regions. However, because DA acts as a relatively slow modulator of cortical neurotransmission, it is unclear whether DA can indeed act to precisely transmit prediction errors to prefrontal cortex (PFC). In light of recent physiological and anatomical evidence, we propose that corelease of glutamate from DA and/or non-DA neurons in the VTA could serve to transmit this temporally precise signal. In contrast, DA acts in a protracted manner to provide spatially and temporally diffuse modulation of PFC pyramidal neurons and interneurons. This modulation occurs first via a relatively rapid depolarization of fast-spiking interneurons that acts on the order of seconds. This is followed by a more protracted modulation of a variety of other ionic currents on timescales of minutes to hours, which may bias the manner in which cortical networks process information. However, the prolonged actions of DA may be curtailed by counteracting influences, which likely include opposing actions at D1 and D2-like receptors that have been shown to be time- and concentration-dependent. In this way, the mesocortical DA system optimizes the characteristics of glutamate, GABA, and DA neurotransmission both within the midbrain and cortex to communicate temporally precise information and to modulate network activity patterns on prolonged timescales.

Abstinence from Cocaine-Induced Conditioned Place Preference Produces Discrete Changes in Glutamatergic Synapses onto Deep Layer 5/6 Neurons from Prelimbic and Infralimbic Cortices.

Glutamatergic signaling in the medial prefrontal cortex (mPFC) plays a critical role in drug addiction and relapse. The mPFC is functionally subdivided into dorsal (prelimbic, PL) and ventral (infralimbic, IL) regions, and evidence suggests a differential role of these two divisions in the control of drug seeking and taking; however, there is a dearth of information on the cocaine-induced adaptations in PL- and IL-mPFC synaptic glutamate transmission and their regulation of behavioral responses to cocaine-associated stimuli. We tested male rats in a cocaine-induced conditioned place preference (CPP) paradigm. In vitro whole-cell recordings were performed at different abstinence intervals to investigate the neuroadaptations in synaptic glutamate transmission in PL- and IL-mPFC deep layer (5/6) pyramidal neurons. Our results show that in naïve animals, PL-mPFC neurons expressed higher frequency of spontaneous events (sEPSCs) than IL-mPFC neurons. Following cocaine-CPP and a short abstinence (SA) period (8 d), we observed decreases in the amplitude of sEPSCs in both mPFC regions. Longer abstinence periods (30 d), resulted in a sustained decrease in the frequency of sEPSCs and an increase in AMPA receptor rectification only in PL-mPFC neurons. In addition, PL-mPFC neurons expressed a decrease in the area under the curve of sEPSCs, suggesting altered receptor activation dynamics. Synaptic glutamate transmission was not significantly different between retested and naïve rats. These results suggest that retention of cocaine-CPP requires differential modulation of glutamate transmission between PL- and IL-mPFC neurons and that these adaptations are dependent on the abstinence interval and reexposure to the cocaine context.

Methamphetamine self-administration modulates glutamate neurophysiology.

World-wide methamphetamine (meth) use is increasing at a rapid rate; therefore, it has become increasingly important to understand the synaptic changes and neural mechanisms affected by drug exposure. In rodents, 6-h access to contingent meth results in an escalation of drug intake and impaired cognitive sequelae typically associated with changes within the corticostriatal circuitry. There is a dearth of knowledge regarding the underlying physiological changes within this circuit following meth self-administration. We assessed pre- and postsynaptic changes in glutamate transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) following daily 6-h meth self-administration. In the mPFC, meth caused postsynaptic adaptations in ionotropic glutamate receptor distribution and function, expressed as a decrease in AMPA/NMDA ratio. This change was driven by an increase in NMDA receptor currents and an increase in GluN2B surface expression. In the NAc, meth decreased the paired-pulse ratio and increased the frequency of spontaneous excitatory postsynaptic currents with no indication of postsynaptic changes. These changes in mPFC synapses and NAc activity begin to characterize the impact of meth on the corticostriatal circuitry.

Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling.

In vivo extracellular recording studies have traditionally shown that dopamine (DA) transiently inhibits prefrontal cortex (PFC) neurons, yet recent biophysical measurements in vitro indicate that DA enhances the evoked excitability of PFC neurons for prolonged periods. Moreover, although DA neurons apparently encode stimulus salience by transient alterations in firing, the temporal properties of the PFC DA signal associated with various behaviors is often extraordinarily prolonged. The present study used in vivo electrophysiological and electrochemical measures to show that the mesocortical system produces a fast non-DA-mediated postsynaptic response in the PFC that appears to be initiated by glutamate. In contrast, short burst stimulation of mesocortical DA neurons that produced transient (<4 s) DA release in the PFC caused a simultaneous reduction in spontaneous firing (consistent with extracellular in vivo recordings) and a form of DA-induced potentiation in which evoked firing was increased for tens of minutes (consistent with in vitro measurements). We suggest that the mesocortical system might transmit fast signals about reward or salience via corelease of glutamate, whereas the simultaneous prolonged DA-mediated modulation of firing biases the long-term processing dynamics of PFC networks.

Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors.

Although methylphenidate (MPH), a catecholaminergic reuptake blocker, is prescribed for attention-deficit/hyperactivity disorder, there is a dearth of information regarding the cellular basis of its actions. To address this issue, we used whole-cell patch-clamp recordings to investigate the roles of various catecholamine receptors in MPH-induced changes in cortical neuron excitability. We bath-applied dopamine or noradrenaline receptor antagonists in combination with MPH to pyramidal cells located in deep layers of the infralimbic and prelimbic prefrontal cortices. Application of MPH (10 microM) by itself increased cortical cell excitability in slices obtained from juvenile rats. This MPH-mediated increase in excitability was lost when catecholamines were depleted with reserpine prior to recording, demonstrating the requirement for a presynaptic monoamine component. Antagonist studies further revealed that stimulation of alpha-2 noradrenergic receptors mediates the MPH-induced increase in intrinsic excitability. Dopamine D1 receptors played no observable role in the actions of MPH. We therefore propose that MPH is acting to increase catecholaminergic tone in the PFC, and thereby increases cortical excitability by mediating the disinhibition of pyramidal cells through mechanisms that may include activation of alpha-2 adrenoreceptors located in interneurons.

Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex.

Typically, D1 and D2 dopamine (DA) receptors exert opposing actions on intracellular signaling molecules and often have disparate physiological effects; however, the factors determining preferential activation of D1 versus D2 signaling are not clear. Here, in vitro patch-clamp recordings show that DA concentration is a critical determinant of D1 versus D2 signaling in prefrontal cortex (PFC). Low DA concentrations (<500 nm) enhance IPSCs via D1 receptors, protein kinase A, and cAMP. Higher DA concentrations (>1 microm) decrease IPSCs via the following cascade: D2-->G(i)-->platelet-derived growth factor receptor--> increase phospholipase C--> increase IP3--> increase Ca2+--> decrease dopamine and cAMP-regulated phosphoprotein-32--> increase protein phosphatase 1/2A--> decrease GABA(A). Blockade of any molecule in the D2-linked pathway reveals a D1-mediated increase in IPSCs, suggesting that D1 effects are occluded at higher DA concentrations by this D2-mediated pathway. Thus, DA concentration, by acting through separate signaling cascades, may determine the relative amount of cortical inhibition and thereby differentially regulate the tuning of cortical networks.

Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats.

A growing body of evidence suggests that structural changes in the cortex may disrupt dopaminergic transmission in circuits involving the prefrontal cortex (PFC) and may contribute to the etiology of schizophrenia. In this study, we utilize a rodent model of neonatal disruption of cortical development using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM). Using intracellular recordings in vivo, we compare the physiology of prefrontal cortical neurons and their responses to topical administration of dopamine (DA) in intact animals and adult rats treated prenatally with MAM. Topical administration of DA hyperpolarized the membrane potential (MP) and decreased the firing rate of neurons recorded in deep layers of the PFC in intact animals. Furthermore, electrical stimulation of the VTA evoked fast onset epsps or long-lasting depolarizations in PFC neurons. In comparison, PFC neurons recorded in MAM-treated animals had significantly faster baseline firing rates. Moreover, topical administration of DA did not affect the MP or firing rate of the neurons in MAM-treated animals. However, MAM-treated animals exhibited an increase in the percentage of neurons responding with long-lasting depolarizations to stimulation of the VTA. The results of this study indicate that PFC neurons in the MAM-treated rats are not responsive to DA administered superficially, while at the same time exhibit greater responsiveness to VTA stimulation. These results are consistent with a rewiring of the corticolimbic system in response to neurodevelopmental insults.

Low-dimensional attractor for neural activity from local field potentials in optogenetic mice.

We used optogenetic mice to investigate possible nonlinear responses of the medial prefrontal cortex (mPFC) local network to light stimuli delivered by a 473 nm laser through a fiber optics. Every 2 s, a brief 10 ms light pulse was applied and the local field potentials (LFPs) were recorded with a 10 kHz sampling rate. The experiment was repeated 100 times and we only retained and analyzed data from six animals that showed stable and repeatable response to optical stimulations. The presence of nonlinearity in our data was checked using the null hypothesis that the data were linearly correlated in the temporal domain, but were random otherwise. For each trail, 100 surrogate data sets were generated and both time reversal asymmetry and false nearest neighbor (FNN) were used as discriminating statistics for the null hypothesis. We found that nonlinearity is present in all LFP data. The first 0.5 s of each 2 s LFP recording were dominated by the transient response of the networks. For each trial, we used the last 1.5 s of steady activity to measure the phase resetting induced by the brief 10 ms light stimulus. After correcting the LFPs for the effect of phase resetting, additional preprocessing was carried out using dendrograms to identify "similar" groups among LFP trials. We found that the steady dynamics of mPFC in response to light stimuli could be reconstructed in a three-dimensional phase space with topologically similar "8"-shaped attractors across different animals. Our results also open the possibility of designing a low-dimensional model for optical stimulation of the mPFC local network.

Acute cocaine administration depresses cortical activity.

Psychostimulants, when administered acutely, produce significant deficits in cognitive tasks. Indeed, there is considerable evidence that acute administration of cocaine alters cellular processes at the level of the nucleus accumbens and the ventral tegmental area (VTA). However, there have been few studies that explore the acute effects of cocaine in the prefrontal cortex (PFC). Here we report that acute cocaine administration in vivo evokes a prolonged membrane depolarization, decreases cortical spontaneous firing, compromises spontaneous membrane bistability, and blunts the VTA-evoked responses in the PFC. Moreover, acute cocaine administration decreases the amplitude of the EPSP-IPSP sequence that precedes the initiation of the Up states in the PFC, therefore compromising the driving force of cortical bistability and thereby cortical excitability.

Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice.

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein encoded by DTNBP1, dysbindin-1, is expressed in forebrain neurons where it interacts with proteins mediating vesicular trafficking and exocytosis. It has been shown that loss of dysbindin-1 results in a decrease in glutamate release in the prefrontal cortex; however the mechanisms underlying this decrease are not fully understood. In order to investigate this question, we evaluated dysbindin-1 null mutant mice, using electrophysiological recordings of prefrontal cortical neurons, imaging studies of vesicles, calcium dynamics and Western blot measures of synaptic proteins and Ca(2+) channels. Dysbindin-1 null mice showed a decrease in the ready releasable pool of synaptic vesicles, decreases in quantal size, decreases in the probability of release and deficits in the rate of endo- and exocytosis compared with wild-type controls. Moreover, the dysbindin-1 null mice show decreases in the [Ca(2+)]i,expression of L- and N-type Ca(2+)channels and several proteins involved in synaptic vesicle trafficking and priming. Our results provide new insights into the mechanisms of action of dysbindin-1.

Optogenetically evoked gamma oscillations are disturbed by cocaine administration.

Drugs of abuse have enormous societal impact by degrading the cognitive abilities, emotional state and social behavior of addicted individuals. Among other events involved in the addiction cycle, the study of a single exposure to cocaine, and the contribution of the effects of that event to the continuous and further use of drugs of abuse are fundamental. Gamma oscillations are thought to be important neural correlates of cognitive processing in the prefrontal cortex (PFC) which include decision making, set shifting and working memory. It follows that cocaine exposure might modulate gamma oscillations, which could result in reduced cognitive ability. Parvalbumin-positive fast-spiking interneurons play an orchestrating role in gamma oscillation induction and it has been shown recently that gamma oscillations can be induced in an anesthetized animal using optogenetic techniques. We use a knock-in mouse model together with optogenetics and in vivo electrophysiology to study the effects of acute cocaine on PFC gamma oscillation as a step toward understanding the cortical changes that may underlie continuous use of stimulants. Our results show that acute cocaine administration increases entrainment of the gamma oscillation to the optogentically induced driving frequency. Our results also suggest that this modulation of gamma oscillations is driven trough activation of D1 receptors. The acute cocaine-mediated changes in mPFC may underlie the enhancement of attention and awareness commonly reported by cocaine users and may contribute to the further use and abuse of psychostimulants.