Inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity reverses behavioral deficits in a rodent model of autism.

Autism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.

STEP inhibition reverses behavioral, electrophysiologic, and synaptic abnormalities in Fmr1 KO mice.

Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, with additional symptoms including attention deficit and hyperactivity, anxiety, impulsivity, and repetitive movements or actions. The majority of FXS cases are attributed to a CGG expansion that leads to transcriptional silencing and diminished expression of fragile X mental retardation protein (FMRP). FMRP, an RNA binding protein, regulates the synthesis of dendritically-translated mRNAs by stalling ribosomal translation. Loss of FMRP leads to increased translation of some of these mRNAs, including the CNS-specific tyrosine phosphatase STEP (STriatal-Enriched protein tyrosine Phosphatase). Genetic reduction of STEP in Fmr1 KO mice have diminished audiogenic seizures and a reversal of social and non-social anxiety-related abnormalities. This study investigates whether a newly discovered STEP inhibitor (TC-2153) could attenuate the behavioral and synaptic abnormalities in Fmr1 KO mice. TC-2153 reversed audiogenic seizure incidences, reduced hyperactivity, normalized anxiety states, and increased sociability in Fmr1 KO mice. Moreover, TC-2153 reduced dendritic spine density and improved synaptic aberrations in Fmr1 KO neuronal cultures as well as in vivo. TC-2153 also reversed the mGluR-mediated exaggerated LTD in brain slices derived from Fmr1 KO mice. These studies suggest that STEP inhibition may have therapeutic benefit in FXS.

Prenatal drug exposure to illicit drugs alters working memory-related brain activity and underlying network properties in adolescence.

The persistence of effects of prenatal drug exposure (PDE) on brain functioning during adolescence is poorly understood. We explored neural activation to a visuospatial working memory (VSWM) versus a control task using functional magnetic resonance imaging (fMRI) in adolescents with PDE and a community comparison group (CC) of non-exposed adolescents. We applied graph theory metrics to resting state data using a network of nodes derived from the VSWM task activation map to further explore connectivity underlying WM functioning. Participants (ages 12-15 years) included 47 adolescents (27 PDE and 20 CC). All analyses controlled for potentially confounding differences in birth characteristics and postnatal environment. Significant group by task differences in brain activation emerged in the left middle frontal gyrus (BA 6) with the CC group, but not the PDE group, activating this region during VSWM. The PDE group deactivated the culmen, whereas the CC group activated it during the VSWM task. The CC group demonstrated a significant relation between reaction time and culmen activation, not present in the PDE group. The network analysis underlying VSWM performance showed that PDE group had lower global efficiency than the CC group and a trend level reduction in local efficiency. The network node corresponding to the BA 6 group by task interaction showed reduced nodal efficiency and fewer direct connections to other nodes in the network. These results suggest that adolescence reveals altered neural functioning related to response planning that may reflect less efficient network functioning in youth with PDE.

STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD. Mutations in PARK2 are a major contributing factor in the early onset of autosomal-recessive juvenile parkinsonism (AR-JP), although the mechanisms by which a disruption in parkin function contributes to the pathophysiology of PD remain unclear. Here we demonstrate that parkin is an E3 ligase for STEP61 (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP61 accumulates in the striatum of human sporadic PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. The increase in STEP61 is associated with a decrease in the phosphorylation of its substrate ERK1/2 and the downstream target of ERK1/2, pCREB [phospho-CREB (cAMP response element-binding protein)]. These results indicate that STEP61 is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP61 levels directly contribute to the pathophysiology of PD.

Effect of multimeric structure of CaMKII in the GluN2B-mediated modulation of kinetic parameters of ATP.

Interaction of GluN2B subunit of N-methyl-D-aspartate receptor with calcium/calmodulin dependent protein kinase II (CaMKII) is critical for the induction of long term potentiation at hippocampal CA3-CA1 synapses. We have previously reported that CaMKII binding to GluN2B increases its affinity but abolishes the cooperativity for ATP. In the present study, we demonstrate that the reduction in S(0.5) for ATP of an individual CaMKII subunit seems to be directly induced by the binding of GluN2B to the same subunit, while any GluN2B induced effects on the cooperativity and maximal velocity would additionally require the CaMKII holoenzyme structure. We measured the apparent kinetic parameters for ATP using an association domain truncated monomeric CaMKII and a heteromultimeric CaMKII (having subunits that are either GluN2B binding defective or ATP binding defective), in the presence of GluN2A or GluN2B substrates. The S(0.5) value for ATP of monomeric CaMKII is reduced ∼ 3 fold by the presence of GluN2B suggesting that the induced change in affinity for ATP is independent of the holoenzyme structure. The heteromultimeric mutant of CaMKII, did not exhibit cooperativity of ATP binding probably because of the interspersing of ATP binding defective subunits in the holoenzyme. In contrast to the wild type holoenzyme, presence of GluN2B increased the V(max) of monomeric CaMKII which resulted in an approximately 4.0 fold increase in the apparent catalytic constant (V(max)/S(0.5)) as compared to GluN2A. The kinetic parameter values of the heteromultimeric CaMKII for ATP, on the other hand, did not show any significant difference between the phosphorylation of GluN2B and GluN2A suggesting that modulation requires binding of GluN2B to the same subunit. Overall, our present study provides insights into the role of multimeric structure of CaMKII in GluN2B-mediated regulation.

fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history.

Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self-administration (SA). Since natural rewards also activate the mesolimbic reward system in a partially overlapping fashion as cocaine, our design also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed-ratio one, long-access schedule (6 h/day for 20 days). A third group of naïve, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with functional magnetic resonance imaging (fMRI) following an intravenous cocaine injection challenge. A strong positive fMRI response, as measured by fractional cerebral blood volume changes relative to baseline (CBV%), was seen in the sedentary control group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. Given that the two SA groups had identical histories of operant training and handling, this region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals.

Abnormal responses to monetary outcomes in cortex, but not in the basal ganglia, in schizophrenia.

Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear. In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain or avoid the indicated loss. Group differences in blood-oxygen-level-dependent responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC). Significant group by outcome valence interactions were observed in the medial and lateral PFC, lateral temporal cortex, and amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients. Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms.

Nicotine modulation of information processing is not limited to input (attention) but extends to output (intention).

RATIONALE: Nicotine influences many cognitive processes, especially those requiring high attentional loads, yet the impact of nicotine on all aspects of information processing has not been well delineated. OBJECTIVE: The aim of the study was to determine the relative behavioral and functional effects of nicotine on dissociable aspects of information processing (i.e., selective attention and motor intention). METHODS: Adult smokers (N = 25) and healthy controls (N = 23) performed the intention/attention task (IAT) twice, during functional magnetic resonance imaging. The IAT assesses the relative differences in performance evoked by prime stimuli that provide information regarding either the correct hand with which to respond (i.e., intentional primes) or the likely location of a target stimulus (i.e., attentional primes). Smokers were scanned 2 h after nicotine (21 mg) or placebo patch placement. The order of nicotine and placebo sessions was randomized and counter-balanced. Controls were also scanned twice, with no patch placement in either session. RESULTS: While drug condition had no significant effect on reaction time, smokers were overall more accurate than controls. Moreover, nicotine significantly increased the response to intentional primes in brain regions known to mediate response readiness, e.g., inferior parietal lobe, supramarginal gyrus, and striatum. CONCLUSIONS: While limited to participant accuracy, these data suggest that the behavioral effects of nicotine in smokers are not only limited to information processing input (i.e., selective attention) but are also generalizable to output functions (i.e., motor intention). Moreover, nicotine's effects on intention appear to be mediated by a facilitation of function in brain regions associated with information processing output.

Patients with schizophrenia have a reduced neural response to both unpredictable and predictable primary reinforcers.

One prevalent theory of learning states that dopamine neurons signal mismatches between expected and actual outcomes, called temporal difference errors (TDEs). Evidence indicates that dopamine system dysfunction is involved in negative symptoms of schizophrenia (SZ), including avolition and anhedonia. As such, we predicted that brain responses to TDEs in dopamine midbrain nuclei and target areas would be abnormal in SZ. A total of 18 clinically stable patients with chronic SZ and 18 controls participated in an fMRI study, which used a passive conditioning task. In the task, the delivery of a small amount of juice followed a light stimulus by exactly 6 s on approximately 75% of 78 total trials, and was further delayed by 4-7 s on the remaining trials. The delayed juice delivery was designed to elicit the two types of TDE signals, associated with the recognition that a reward was omitted at the expected time, and delivered at an unexpected time. Main effects of TDE valence and group differences in the positive-negative TDE contrast (unexpected juice deliveries-juice omissions) were assessed through whole-brain and regions of interest (ROI) analyses. Main effects of TDE valence were observed for the entire sample in the midbrain, left putamen, left cerebellum, and primary gustatory cortex, bilaterally. Whole-brain analyses revealed group differences in the positive-negative TDE contrast in the right putamen and left precentral gyrus, whereas ROI analyses revealed additional group differences in the midbrain, insula, and parietal operculum, on the right, the putamen and cerebellum, on the left, and the frontal operculum, bilaterally. Further, these group differences were generally driven by attenuated responses in patients to positive TDEs (unexpected juice deliveries), whereas responses to negative TDEs (unexpected juice omissions) were largely intact. Patients also showed reductions in responses to juice deliveries on standard trials, and more blunted reinforcer responses in the left putamen corresponded to higher ratings of avolition. These results provide evidence that SZ patients show abnormal brain responses associated with the processing of a primary reinforcer, which may be a source of motivational deficits.

Divided versus selective attention: evidence for common processing mechanisms.

The current study revisited the question of whether there are brain mechanisms specific to divided attention that differ from those used in selective attention. Increased neuronal activity required to simultaneously process two stimulus dimensions as compared with each separate dimension has often been observed, but rarely has activity induced by a divided attention condition exceeded the sum of activity induced by the component tasks. Healthy participants performed a selective-divided attention paradigm while undergoing functional Magnetic Resonance Imaging (fMRI). The task required participants to make a same-different judgment about either one of two simultaneously presented stimulus dimensions, or about both dimensions. Performance accuracy was equated between tasks by dynamically adjusting the stimulus display time. Blood Oxygenation Level Dependent (BOLD) signal differences between tasks were identified by whole-brain voxel-wise comparisons and by region-specific analyses of all areas modulated by the divided attention task (DIV). No region displayed greater activation or deactivation by DIV than the sum of signal change by the two selective attention tasks. Instead, regional activity followed the tasks' processing demands as reflected by reaction time. Only a left cerebellar region displayed a correlation between participants' BOLD signal intensity and reaction time that was selective for DIV. The correlation was positive, reflecting slower responding with greater activation. Overall, the findings do not support the existence of functional brain activity specific to DIV. Increased activity appears to reflect additional processing demands by introducing a secondary task, but those demands do not appear to qualitatively differ from processes of selective attention.