Word and Tone Working Memory Deficits in Schizophrenia

126

Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val 108/158 Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N ¼ 14) and of normal controls (N ¼ 15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F ¼ 2.68, df ¼ 4,108, Po0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (Po0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val 108/158 Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia.

Section: Introductionmentioning

confidence: 98%

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Matsumoto

Weickert

Beltaifa

et al. 2003

126

“…In subjects with schizophrenia, the rapid initial phases of transfer and processing of sensory information within the auditory cortex are impaired (McCarley et al, 1991;Javitt et al, 1994Javitt et al, , 1995Javitt et al, , 1997bJavitt et al, , 2000Rabinowicz et al, 2000). These impairments are manifest as the reduced ability to discriminate tones Strous et al, 1995;Wexler et al, 1998) and as deficits in recognition of prosody (Leitman et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

Sweet

Henteleff

Zhang

et al. 2008

259

221

We have previously identified reductions in mean pyramidal cell somal volume in deep layer 3 of BA 41 and 42 and reduced axon terminal density in deep layer 3 of BA 41. In other brain regions demonstrating similar deficits, reduced dendritic spine density has also been identified, leading us to hypothesize that dendritic spine density would also be reduced in BA 41 and 42. Because dendritic spines and their excitatory inputs are regulated in tandem, we further hypothesized that spine density would be correlated with axon terminal density. We used stereologic methods to quantify a marker of dendritic spines, spinophilin-immunoreactive (SP-IR) puncta, in deep layer 3 of BA 41 and 42 of 15 subjects with schizophrenia, each matched to a normal comparison subject. The effect of long-term haloperidol exposure on SP-IR puncta density was evaluated in nonhuman primates. SP-IR puncta density was significantly lower by 27.2% in deep layer 3 of BA 41 in the schizophrenia subjects, and by 22.2% in deep layer 3 of BA 42. In both BA 41 and 42, SP-IR puncta density was correlated with a marker of axon terminal density, but not with pyramidal cell somal volume. SP-IR puncta density did not differ between haloperidol-exposed and control monkeys. Lower SP-IR puncta density in deep layer 3 of BA 41 and 42 of subjects with schizophrenia may reflect concurrent reductions in excitatory afferent input. This may contribute to impairments in auditory sensory processing that are present in subjects with schizophrenia.

“…For example, schizophrenic patients show deficits in auditory sensory (echoic) memory, which encodes and maintains representations of simple physical features of auditory stimuli (eg pitch, intensity) for up to 30 s following stimulus presentation (Lu et al, 1992). These deficits are manifested in an impaired ability to match tones following a brief delay (Javitt et al, 1997;Strous et al, 1995;Wexler et al, 1998) and most likely represent dysfunction at the level of the auditory sensory cortex (Rabinowicz et al, 2000). Consequently, these deficits can also be demonstrated in an abnormal reduction of an event-related potential (ERP) component that is generated in auditory sensory areas (Alho, 1995;Frodl-Bauch et al, 1997;Korzyukov et al, 1999;Näätänen and Alho, 1995a;Tiitinen et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

Umbricht

Vollenweider

Schmid

et al. 2003

169

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)Fmeasures of auditory and visual context-dependent information processingFin a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT 2A receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT 2A agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT 2A and NMDAR-related neurotransmission.