Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients

Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia.

Decreased Reelin Expression in the Left Prefrontal Cortex (BA9) in Chronic Schizophrenia Patients

Background: Reelin is under epigenetic control and has been reported to be decreased in cortical regions in schizophrenia. Methods: To establish if expression of reelin is altered in specific cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of reelin in a postmortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral postmortem samples (dorsolateral prefrontal cortex BA9 and BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus, CA4, mediodorsal nucleus of the thalamus) from 12 schizophrenia patients with 13 normal subjects investigating gene expression of reelin in the gray and white matter of both hemispheres by in situ-hybridization. Results: The left prefrontal area (BA9) of schizophrenia patients revealed a decreased expression of reelin-mRNA of 29.1% in the white (p = 0.022) and 13.6% in the gray matter (p = 0.007) compared to the control group. None of the other regions examined showed any statistically significant differences. Conclusion: Since reelin is responsible for migration and synapse formation, the decreased gene expression of reelin in the left prefrontal area of schizophrenia patients points to neurodevelopmental deficits in neuronal migration and synaptic plasticity. However, our study group was small, and results should be verified using larger samples. Copyright (C) 2012 S. Karger AG, Basel

Muscarinic and Nicotinic Modulation of Thalamo-Prefrontal Cortex Synaptic Pasticity In Vivo

The mediodorsal nucleus of the thalamus (MD) is a rich source of afferents to the medial prefrontal cortex (mPFC). Dysfunctions in the thalamo-prefrontal connections can impair networks implicated in working memory, some of which are affected in Alzheimer disease and schizophrenia. Considering the importance of the cholinergic system to cortical functioning, our study aimed to investigate the effects of global cholinergic activation of the brain on MD-mPFC synaptic plasticity by measuring the dynamics of long-term potentiation (LTP) and depression (LTD) in vivo. Therefore, rats received intraventricular injections either of the muscarinic agonist pilocarpine (PILO; 40 nmol/mu L), the nicotinic agonist nicotine (NIC; 320 nmol/mu L), or vehicle. The injections were administered prior to either thalamic high-frequency (HFS) or low-frequency stimulation (LFS). Test pulses were applied to MD for 30 min during baseline and 240 min after HFS or LFS, while field postsynaptic potentials were recorded in the mPFC. The transient oscillatory effects of PILO and NIC were monitored through recording of thalamic and cortical local field potentials. Our results show that HFS did not affect mPFC responses in vehicle-injected rats, but induced a delayed-onset LTP with distinct effects when applied following PILO or NIC. Conversely, LFS induced a stable LTD in control subjects, but was unable to induce LTD when applied after PILO or NIC. Taken together, our findings show distinct modulatory effects of each cholinergic brain activation on MD-mPFC plasticity following HFS and LFS. The LTP-inducing action and long-lasting suppression of cortical LTD induced by PILO and NIC might implicate differential modulation of thalamo-prefrontal functions under low and high input drive.

Increased variability of motor cortical excitability to transcranial magnetic stimulation in migraine: a new clue to an old enigma

Increased, decreased or normal excitability to transcranial magnetic stimulation (TMS) has been reported in the motor (M1) and visual cortices of patients with migraine. Light deprivation (LD) has been reported to modulate M1 excitability in control subjects (CS). Still, effects of LD on M1 excitability compared to exposure to environmental light exposure (EL) had not been previously described in patients with migraine (MP). To further our knowledge about differences between CS and MP, regarding M1 excitability and effects of LD on M1 excitability, we opted for a novel approach by extending measurement conditions. We measured motor thresholds (MTs) to TMS, short-interval intracortical inhibition, and ratios between motor-evoked potential amplitudes and supramaximal M responses in MP and CS on two different days, before and after LD or EL. Motor thresholds significantly increased in MP in LD and EL sessions, and remained stable in CS. There were no significant between-group differences in other measures of TMS. Short-term variation of MTs was greater in MP compared to CS. Fluctuation in excitability over hours or days in MP is an issue that, until now, has been relatively neglected. The results presented here will help to reconcile conflicting observations.

Novelty, but Not Operant Aversive Learning, Enhances Fos and Egr-1 Expression in the Medial Prefrontal Cortex and Hippocampal Areas of Rats

Immediate early genes (IEG) are presumed to be activated in response to stress, novelty, and learning. Evidence supports the involvement of prefrontal and hippocampal areas in stress and learning, but also in the detection of novel events. This study examined whether a previous experience with shocks changes the pattern of Fos and Egr-1 expression in the medial prefrontal cortex (mPFC), the hippocampal cornus ammonis 1 (CA1), and dentate gyrus (DG) of adult male Wistar rats that learned to escape in an operant aversive test. Subjects previously exposed to inescapable footshocks that learned to escape from Shocks were assigned to the treated group (EXP). Subjects from Group Novelty (NOV) rested undisturbed during treatment and also learned to escape in the test. The nonshock group (NSH) rested undisturbed in both sessions. Standard immunohistochemistry procedures were used to detect the proteins in brain sections. The results show that a previous experience with shocks changed the pattern of IEG expression, then demonstrating c-fos and egr-1 induction as experience-dependent events. Compared with NSH and EXP an enhanced Fos expression was detected in the mPFC and CA1 subfield of Group NOV, which also exhibited increased Egr-1 expression in the mPFC and DG in comparison to NSH. No differences were found in the DG for Fos, or in the CA1 for Egr-1. Novelty, and not the operant aversive escape learning, seems to have generated IEG induction. The results suggest novel stimuli as a possible confounding factor in studies on Fos and/or Egr-1 expression in aversive conditions.

Motor recovery and synaptic preservation after ventral root avulsion and repair with a fibrin sealant derived from snake venom

Background: Ventral root avulsion is an experimental model of proximal axonal injury at the central/peripheral nervous system interface that results in paralysis and poor clinical outcome after restorative surgery. Root reimplantation may decrease neuronal degeneration in such cases. We describe the use of a snake venom-derived fibrin sealant during surgical reconnection of avulsed roots at the spinal cord surface. The present work investigates the effects of this fibrin sealant on functional recovery, neuronal survival, synaptic plasticity, and glial reaction in the spinal motoneuron microenvironment after ventral root reimplantation. Methodology/Principal Findings: Female Lewis rats (7 weeks old) were subjected to VRA and root replantation. The animals were divided into two groups: 1) avulsion only and 2) replanted roots with fibrin sealant derived from snake venom. Post-surgical motor performance was evaluated using the CatWalk system twice a week for 12 weeks. The rats were sacrificed 12 weeks after surgery, and their lumbar intumescences were processed for motoneuron counting and immunohistochemistry (GFAP, Iba-1 and synaptophysin antisera). Array based qRT-PCR was used to evaluate gene regulation of several neurotrophic factors and receptors as well as inflammatory related molecules. The results indicated that the root reimplantation with fibrin sealant enhanced motor recovery, preserved the synaptic covering of the motoneurons and improved neuronal survival. The replanted group did not show significant changes in microglial response compared to VRA-only. However, the astroglial reaction was significantly reduced in this group. Conclusions/Significance: In conclusion, the present data suggest that the repair of avulsed roots with snake venom fibrin glue at the exact point of detachment results in neuroprotection and preservation of the synaptic network at the microenvironment of the lesioned motoneurons. Also such procedure reduced the astroglial reaction and increased mRNA levels to neurotrophins and anti-inflammatory cytokines that may in turn, contribute to improving recovery of motor function.