Impairment of working memory maintenance and response in schizophrenia: functional magnetic resonance imaging evidence.

Background: Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases.

Methods: Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load.

Ultrastructural localization of calcyon in the primate cortico-basal ganglia-thalamocortical loop.

Recent observations suggest that calcyon, a novel single transmembrane protein implicated in schizophrenia and attention-deficit/hyperactivity disorder, regulates clathrin-mediated endocytosis in brain. To explore the role of calcyon in neurotransmission, we investigated its distribution in the neuropil of the primate prefrontal cortex (PFC), striatum (STR) and mediodorsal thalamic nucleus (MD), three brain regions implicated in these neuropsychiatric disorders. Calcyonimmunoreactivity revealed by immunoperoxidase technique, was localized in both pre- and postsynaptic structures including axons, spines and dendrites, as well as myelinated fibers and astroglial processes in all the three brain regions.

Modulation of dorsolateral prefrontal delay activity during self-organized behavior.

The regulation of cognitive activity relies on the flexibility of prefrontal cortex functions. To study this mechanism we compared monkey dorsolateral prefrontal activity in two different spatial cognitive tasks: a delayed response task and a self-organized problem-solving task. The latter included two periods, a search by trial and error for a correct response, and a repetition of the response once discovered.

Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate prefrontal cortex.

Much of our knowledge on trafficking of neurotransmitter receptors derives from heterologous expression systems and neurons in vitro. Understanding these dynamics in vivo for dopamine receptors, and D2 receptors (D2Rs) in particular, presents a foremost challenge as their pharmacological manipulation underlies antipsychotic medications and drug abuse, which may in turn alter response to endogenous dopamine. Here we present the first ultrastructural evidence of clathrin-mediated endocytosis of D2Rs or any other neurotransmitter receptor in the primate brain.

Amphetamine sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons in the non-human primate.

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3(1/2) years postsensitization, sensitized, and AMPH-naïve control monkeys were killed.

Heterogeneity in the pyramidal network of the medial prefrontal cortex.

The prefrontal cortex is specially adapted to generate persistent activity that outlasts stimuli and is resistant to distractors, presumed to be the basis of working memory. The pyramidal network that supports this activity is unknown. Multineuron patch-clamp recordings in the ferret medial prefrontal cortex showed a heterogeneity of synapses interconnecting distinct subnetworks of different pyramidal cells.

NMDA receptor-mediated epileptiform persistent activity requires calcium release from intracellular stores in prefrontal neurons.

Various normal and pathological forms of synchronized population activity are generated by recurrent excitation among pyramidal neurons in the neocortex. However, the intracellular signaling mechanisms underlying this activity remain poorly understood. In this study, we have examined the cellular properties of synchronized epileptiform activity in the prefrontal cortex with particular emphasis on a potential role of intracellular calcium stores.

Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex.

Structures of the cerebral cortex expressing the D2 dopamine receptor subtype (D2) are important sites of action of antipsychotic drugs. It has also been repeatedly suggested that the prefrontal cortex plays a significant role in neuropsychiatric disorders, including schizophrenia. Here, by using single and double immunohistochemical techniques with electron microscopy, we investigated in the primate prefrontal cortex the ultrastructural localization of D2 and we compared it with that of the neuronal calcium sensor-1 (NCS-1), a neuron-specific calcium-binding and D2-interacting protein.

Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex.

Background: Amphetamine (AMPH) sensitization in monkeys produces long-lasting behavioral changes that model positive (hallucinatory-like behaviors) and negative (psychomotor depression) symptoms of schizophrenia. The extent to which this model produces the core deficit in schizophrenia--working memory impairment--is unknown.

Methods: Two groups of rhesus monkeys were sensitized to AMPH over 6 weeks.

Morphometric characterization of synapses in the primate prefrontal cortex formed by afferents from the mediodorsal thalamic nucleus.

The main thalamic afferentation of the prefrontal cortex (PFC) originates in the mediodorsal nucleus (MD). Although it is suggested that this pathway is affected in schizophrenia, there is a lack of functional and structural data regarding its synaptic organization. The scope of this study was to characterize the ultrastructural features of thalamocortical synapses formed by afferents from the MD by applying anterograde tract tracing, immunohistochemical detection of parvalbumin (PV, a probable marker of thalamocortical endings), and quantitative electron microscopic techniques to the PFC of the macaque monkey.

Differential anterior prefrontal activation during the recognition stage of a spatial working memory task.

Neuroimaging studies commonly show widespread activations in the prefrontal cortex during various forms of working memory and long-term memory tasks. However, the anterior prefrontal cortex (aPFC, Brodmann area 10) has been mainly associated with retrieval in episodic memory, and its role in working memory is less clear. We conducted an event-related functional magnetic resonance imaging study to examine brain activations in relation to recognition in a spatial delayed-recognition task.

Presynaptic D1 dopamine receptors in primate prefrontal cortex: target-specific expression in the glutamatergic synapse.

Dopaminergic modulation of glutamate neurotransmission in prefrontal cortex (PFC) microcircuits is commonly perceived as a basis for cognitive operations. Yet it appears that although the control of recurrent excitation between deep-layer prefrontal pyramids may involve presynaptic and postsynaptic D1 receptor (D1R) mechanisms, pyramid-to-interneuron communication will engage a postsynaptic D1R component. The substrate underlying such target-specific neuromodulatory patterns was investigated in the infragranular PFC with immunoelectron microscopy for D1R and parvalbumin, a marker for fast-spiking interneurons.

Direct and indirect effects of fetal irradiation on cortical gray and white matter volume in the macaque.

Background: Schizophrenia is associated with reductions in thalamic neuronal number and cortical gray matter volume. Exposure of nonhuman primates to x-irradiation in early gestation has previously been shown to decrease thalamic volume and neuronal number. Here we examine whether early gestational irradiation also results in cortical volume reduction.

Comparison of oculomotor neuronal activity in paralaminar and mediodorsal thalamus in the rhesus monkey.

We previously reported that neurons in the mediodorsal thalamic nucleus (MD) are topographically organized and express spatial and nonspatial coding properties similar to those of the prefrontal areas with which they are connected. In the course of mapping the dorsal thalamus, we also studied neurons in a subset of thalamic nuclei (the caudal part of the ventral lateral nucleus (VLc), the oral part of the ventral posterior lateral nucleus (VPLo), the parvocellular part of the ventral anterior nucleus (VApc)) lateral to the MD and just across the internal medullary lamina. We compared these "paralaminar" neurons to MD neurons by having monkeys perform the same spatial and nonspatial cognitive tasks as those used to investigate the MD; these included two saccadic tasks-one requiring delayed and the other immediate responses-and one picture fixation task.

Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia.

Background And Rationale: Working memory performance is considered to be a core deficit in schizophrenia and the best predictor of social reintegration and propensity for relapse. This cardinal cognitive process is critical for human reasoning and judgment and depends upon the integrity of prefrontal function. Prefrontal dysfunction in schizophrenia has been linked to altered dopaminergic and glutamatergic transmission.

Microdomains for dopamine volume neurotransmission in primate prefrontal cortex.

The explicit yet enigmatic involvement of dopamine in cortical physiology is in part volumetric (beyond the synapse), as is apparently the action of neuroleptics targeting dopamine receptors. The notion that nonsynaptic neuronal membranes would translate extracellular dopamine into receptor-specific spatiotemporal downstream signaling, similar to the chemical synapse, is intriguing. Here, we report that dopamine D5 (but not D1 or D2) receptors in the perisomatic plasma membrane of prefrontal cortical neurons form discrete and exclusively extrasynaptic microdomains with inositol 1,4,5-trisphosphate-gated calcium stores of subsurface cisterns and mitochondria.

Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction.

Background And Rationale: Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D(1) receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D(1) stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia.

Objectives: This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models.

D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons.

The efficacy of antipsychotics in the treatment of schizophrenia depends on their ability to block dopamine (DA) D2 receptors. D2 receptor excitatory mediation of glutamatergic receptors has been implicated in in vivo studies. However, D2 receptor enhancement of glutamatergic transmission has rarely been reported in slice recordings.

Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation.

A natural consequence of aging is a loss of dopamine function and associated deficits in working memory in both human and nonhuman primates. Specifically, deficiency of D1 receptor signaling has been implicated in age-related cognitive decline. Here, we report that an intermittent, sensitizing regimen of the D1 dopamine agonist ABT-431 dramatically enhances working memory performance in aged rhesus monkeys, while either producing impairment or having little effect on performance in young adult monkeys.

Selective D2 receptor actions on the functional circuitry of working memory.

Prefrontal neurons engaged by working memory tasks express a sequence of phasic and tonic activations linked to a train of sensory, mnemonic, and response-related events. Here, we report that the dopamine D2 receptor selectively modulates the neural activities associated with memory-guided saccades in oculomotor delayed-response tasks yet has little or no effect on the persistent mnemonic-related activity, which is instead modulated by D1 receptors. This associates the D2 receptor with a specific component of working memory circuitry and fractionates the modulatory effects of D1 and D2 receptors on the neural machinery of a cognitive process.

Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.

A conspicuous feature of cortical organization is the wide diversity of inhibitory interneurons; their differential computational functions remain unclear. Here we propose a local cortical circuit in which three major subtypes of interneurons play distinct roles. In a model designed for spatial working memory, stimulus tuning of persistent activity arises from the concerted action of widespread inhibition mediated by perisoma-targeting (parvalbumin-containing) interneurons and localized disinhibition of pyramidal cells via interneuron-targeting (calretinin-containing) interneurons.

Evidence for progression in frontal cortical pathology in late-stage Huntington's disease.

Atrophy of the cerebral cortex in Huntington's disease is regionally heterogeneous and progressive, involving the entire cerebral mantle in terminal stages. Here, two areas (9 and 46) of the dorsolateral prefrontal cortex were analyzed in 11 late-stage (grades 3 or 4) Huntington's diseased patients and 8 normal control subjects. We used a 3-dimensional cell counting method to assess laminar cell density, number, and width.

Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling.

Abnormal activity of the dopamine system has been implicated in several psychiatric and neurological illnesses; however, lack of knowledge about the precise sites of dopamine dysfunction has compromised our ability to improve the efficacy and safety of dopamine-related drugs used in treatment modalities. Recent work suggests that dopamine transmission is regulated via the concerted efforts of a cohort of cytoskeletal, adaptor and signaling proteins called dopamine receptor-interacting proteins (DRIPs). The discovery that two DRIPs, calcyon and neuronal Ca(2+) sensor 1 (NCS-1), are upregulated in schizophrenia highlights the possibility that altered protein interactions and defects in Ca(2+) homeostasis might contribute to abnormalities in the brain dopamine system in neuropsychiatric diseases.