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Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder (SSD) and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes - processing speed, whole-brain white matter fractional anisotropy (FA) and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of

Background Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age-related decline in FA values. In the largest mega-analysis to date, we tested if differences in the trajectories of WM tract development influenced patient–control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging. Methods Three cohorts of schizophrenia patients (total n = 177) and controls (total n = 249; age = 18-61 years) were ascertained with three 3T Siemens MRI scanners. Whole-brain and regional FA values were extracted using ENIGMA-DTI protocols. Statistics were evaluated using mega- and meta-analyses to detect effects of diagnosis and age-by-diagnosis interactions. Results In mega-analysis of whole-brain averaged FA, schizophrenia patients had lower FA (P = 10−11) and faster age-related decline in FA (P = 0.02) compared with controls. Tract-specific heterochronicity measures, that is, abnormal rates of adolescent maturation and aging explained approximately 50% of the regional variance effects of diagnosis and age-by-diagnosis interaction in patients. Interactive, three-dimensional visualization of the results is available at www.enigma-viewer.org. Conclusion WM tracts that mature later in life appeared more sensitive to the pathophysiology of schizophrenia and were more susceptible to faster age-related decline in FA values. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Many aspects of the dopamine (DA) system mature during adolescence. For example, the DA modulation of glutamate responses in the rat prefrontal cortex (PFC) acquires adult characteristics during late adolescence. In the striatum, D₁ receptors modulate NMDA responses, but whether this behaviorally important interaction matures during adolescence is not known. Here, we tested whether the D₁ agonist SKF38393 affects NMDA actions on nucleus accumbens medium spiny neuron (MSN) excitability in slices from juvenile and young adult rats. NMDA dose-dependently increased excitability in both age groups, and the D₁ agonist produced a marginal increase of MSN excitability. In juvenile slices, the most common interaction was a downregulation of NMDA effects on excitability by the D₁ agonist, whereas in most adult MSN, the D₁ agonist increased NMDA effects on MSN excitability. These results suggest that D₁-NMDA receptor interactions in the nucleus accumbens change during adolescence, a change that may result in different processing of reward functions during this critical developmental stage.

Hippocampal inputs to the nucleus accumbens (NA) have been proposed to implement a gating mechanism by driving NA medium spiny neurons (MSNs) to depolarized up states that facilitate action potential firing in response to brief activation of the prefrontal cortex (PFC). Brief PFC stimulation alone, on the other hand, could not drive NA up states. As these studies were conducted using single-pulse PFC stimulation, it remains possible that PFC activation with naturalistic, bursty patterns can also drive up states in NA MSNs. Here, we assessed NA responses to PFC stimulation with a pattern similar to what is typically observed in awake animals during PFC-relevant behaviors. In vivo intracellular recordings from NA MSNs revealed that brief 20-50 Hz PFC stimulus trains evoked depolarizations that were similar to spontaneous up states in NA MSNs and were sustained beyond stimulus offset. Similar train stimulation of corticoaccumbens afferents in a parasagittal slice preparation evoked large amplitude depolarizations in NA MSNs that were sustained during stimulation but decayed rapidly following stimulation offset, suggesting that activation of cortical afferents can drive MSN depolarizations but other mechanisms may contribute to sustaining up states. These data suggest that NA MSNs integrate temporal features of PFC activation and that the NA gating model can be reformulated to include a PFC-driven gating mechanism during periods of high PFC firing, such as during cognitively demanding tasks. Synapse 63:173-180, 2009. (c) 2008 Wiley-Liss, Inc.

Organotypic cocultures of striatum, cortex, and ventral mesencephalon were used to study the anatomical and physiological development of striatal neurons in the presence or absence of cortical and nigral (SN/VTA) inputs. Striatum and cortex were dissected from prenatal (E18-E22) or early postnatal (P0-P2) rats, and SN/VTA was dissected from E14-15 fetuses; pieces were maintained up to 3 weeks in static slice culture. Triple cocultures containing SN/VTA exhibited rapid and robust dopamine (DA) innervation of the striatum in a patchy pattern, and homogeneous distribution within the cortical piece, regardless of the orientations of the three pieces. DA fibers within the striatal piece overlapped striatal patch neurons, marked by DARPP-32 immunoreactivity, in striatal cultures prepared from all age rats, but development most analogous to that seen in vivo was observed with the use of late prenatal (E20-E22) striatum. The patch/matrix organization was maintained in cultures prepared from late prenatal striatum in the presence of cortical and nigrostriatal DA afferents. In addition, a more complete transition to a patchy organization was observed in E18/19 striatal cultures in the presence of cortical and DA innervation. Electrophysiological recording demonstrated the presence of both spontaneous and cortically evoked activity in striatal medium spiny neurons; this activity was greatly influenced by the presence of DA innervation. These findings demonstrate the importance of afferent innervation in the maturation of striatal neurons in organotypic cultures.

The dopamine modulation of neuronal excitability in the prefrontal cortex (PFC) changes during critical late periods of postnatal development. In particular, D2 receptors activate fast-spiking interneurons after, and not before, adolescence. To test the functional impact of this change, we investigated the effects of dopamine agonists on PFC excitatory synaptic transmission with whole-cell recordings from deep-layer pyramidal neurons in brain slices obtained from prepubertal [postnatal day (PD) 28–35] and postpubertal (PD > 51) rats. Electrical stimulation of superficial layers elicited a fast AMPA/kainate excitatory postsynaptic potential (EPSP). In the adult PFC, the D2 agonist quinpirole decreased EPSP amplitude, an effect that lasted for at least 25 min after drug washout and was blocked by the D2 antagonist eticlopride. The late component of this effect was blocked by the GABA-A antagonist picrotoxin without affecting the early inhibition. Quinpirole also decreased EPSP amplitude in deep-layer pyramidal neurons from prepubertal rats, but this response was not affected by picrotoxin. A D1 agonist, on the other hand, did not affect the pyramidal neuron EPSP. These results indicate that D2, not D1, receptors attenuate local excitatory synaptic transmission in the adult PFC, and this effect of D2 involves a recruitment of local GABAergic activity. Synapse 61:843–850, 2007. © 2007 Wiley-Liss, Inc.

In vivo, cortical neurons and striatal medium spiny neurons (MSN) display robust subthreshold depolarizations (Up states) during which they are enabled to fire action potentials. In the cortex, Up states are believed to occur simultaneously in a neuronal ensemble and to be sustained by local network interactions. It is known that MSN are impelled into the Up state by extra-striatal (primarily cortical) inputs, but the mechanisms that sustain and determine the end of striatal Up states are still debated. Furthermore, it has not been established if brisk perturbations of ongoing cortical oscillations alter rhythmic transitions between Up and Down states in striatal neurons. Here we report that MSN Up states terminate abruptly when persistent activity in cortical ensembles providing afferents to a given striatal region is turned off by local electrical stimulation or ends spontaneously. In addition, we found that phase perturbations in MSN membrane potential slow oscillations induced by cortical stimulation replicate the stimulus-induced dynamics of spiking activity in cortical ensembles. Overall, these results suggest that striatal Up states are single-cell subthreshold representations of episodes of persistent spiking in cortical ensembles. A precise spatial and temporal alignment between episodes of cortical persistent activity and striatal Up states would allow MSN to detect specific cortical inputs embedded within a more general cortical signal.

Prefrontal cortical (PFC) pyramidal neurons (PN) and fast spiking inter-neurons (FSI) receive dopaminergic (DA) and non-DA inputs from the ventral tegmental area (VTA). Although the responses of PN to VTA stimulation and DA administration have been extensively studied, little is known about the response of FSI to mesocortical activation. We explored this issue using single and double in vivo juxtacellular recordings of medial PFC PN and FSI with chemical VTA stimulation. Electrophysiological characteristics combined with Neurobiotin staining and parvalbumin immunohistochemistry allowed identification of recorded cells as FSI or PN. NMDA injection into the VTA increased firing in all FSI tested (n = 7), whereas most PN (7/11) responded with an inhibition. Furthermore, FSI excitation matching the temporal course of PN inhibition was observed with FSI–PN paired recordings (n = 5). These divergent electrophysiological responses to mesocortical activation could reflect PFC GABAergic inter-neurons contributing to silencing PN. Thus, the mesocortical system could provide a critical control of PFC circuits by simultaneously affecting FSI and PN firing.

Dopamine may exert different actions depending on a number of factors. A common view is that D 1 receptors may be responsible for excitatory actions whereas D 2 receptors are involved in inhibitory actions. However, thisposition cannot be reconciled with several findings indicating otherwise. The role of dopamine on forebrain neural ensembles may be better understood in the light of functional states of the system. Pyramidal cortical neurons and striatal medium spiny neurons alternate between two membrane potential states ('up' and 'down') that could shape dopamine actions. It is proposed that D 1 receptors can act as state-stabilizers by sustaining up states and thereby facilitating plasticity mechanisms by providing postsynaptic depolarization and increasing NMDA function. In this way, dopamine can sustain activity in depolarized units. This action is accompanied by a decrease in cell firing (perhaps mediated by D 2 receptors), which renders the cells responsive only to strong stimuli. The result would be a net increase in signal-to-noise ratio in a selected assembly of neurons.

Pennartz et al. have proposed that functions of the nucleus accumbens (NA) are subserved by the activity of ensembles of neurons rather than by an overall neuronal activation. Indeed, the NA is a site of convergence for a large number of inputs from limbic structures that may modulate the flow of prefrontal cortical information and contribute to defining such ensembles, as exemplified in the ability of hippocampal input to gate cortical throughput in the nucleus accumbens. NA neurons exhibit a bistable membrane potential, characterized by a very negative resting membrane potential (down state), periodically interrupted by plateau depolarizations (up state), during which the cells may fire in response to cortical inputs. A dynamic ensemble can be the result of a distributed set of neurons in their up state, determined by the moment-to-moment changes in the spatial distribution of hippocampal inputs responsible for transitions to the up state. Ensembles may change as an adaptation to the contextual information provided by the hippocampal input. Furthermore, for dynamic ensembles to be functionally relevant, the model calls for near synchronous transitions to the up state in a group of neurons. This can be accomplished by the cell-to-cell transfer of information via gap junctions, a mechanism that can allow for a transfer of slow electrical signals, including "up" events between coupled cells. Furthermore, gap junction permeability is tightly modulated by a number of factors, including levels of dopamine and nitric oxide, and cortical inputs, allowing for fine-tuning of this synchronization of up events. The continuous selection of such dynamic ensembles in the NA may be disputed in schizophrenia, resulting in an inappropriate level of activity of thalamocortical systems.

The morphology and electrophysiological properties of neurons in the nucleus accumbens were studied using intracellular recording techniques in rat brain slices maintained in vitro. Neurons were subdivided according to their location in the shell or core region of the nucleus accumbens. Most of the cells in both regions had small to medium-sized (15.8 +/- 2.8 microns) somata with densely spinous dendrites, somewhat similar to the striatal medium spiny neuron. However, minor morphological differences between neurons from accumbens core and shell regions were found, such as fewer primary dendrites in shell neurons than in the core (3.8 +/- 0.8 vs. 4.4 +/- 1.0) and the spatial organization of their dendritic trees. In general, the passive membrane properties of neurons in each region were similar. However, shell neurons appeared to be less excitable in nature, as suggested by (1) a faster time constant, (2) the absence of TTX-insensitive events resembling low-threshold spikes, and (3) the lower probability of evoking spikes in shell neurons by stimulation of amygdaloid or cortical afferents in comparison to the responses of core neurons to cortical afferent stimulation. In most nucleus accumbens neurons the action potentials evoked by membrane depolarization were preceded by a slow Ca(2+)-dependent depolarization and showed firing-frequency adaptation. Following TTX administration, all-or-none spike-like events resembling high-threshold calcium spikes were observed in both regions. In summary, except for minor differences, most of the properties of core and shell neurons are similar, supporting their characterization as subdivisions of a single structure. Therefore, differences in the functional properties of these neuronal populations are likely to be due to their distinct connectivity patterns.