Rationale
Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating ...brain levels of kynurenic acid (KYNA). KYNA’s effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor.
Objectives
The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP).
Methods
DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site.
Results
Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals.
Conclusions
These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
Rationale
Levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine receptors (α7nAChRs) and antagonist at glutamatergic
N
-methyl-
d
-aspartate receptors ...(NMDARs), are elevated in the brain of patients with schizophrenia (SZ). In rats, dietary exposure to KYNA’s immediate precursor kynurenine during the last week of gestation produces neurochemical and cognitive deficits in adulthood that resemble those seen in patients with SZ.
Objectives
The present experiments examined whether prenatal kynurenine exposure results in
age-dependent
changes in the kynurenine pathway (KP), expression of selected receptors, and cognitive function.
Methods
Pregnant dams were fed unadulterated mash (progeny = ECON) or mash containing kynurenine (100 mg/day; progeny = EKYN) from embryonic day (ED) 15 to 22. Male offspring were assessed as juveniles, i.e., prior to puberty (postnatal day PD 32), or as adults (PD70) for brain KYNA levels, α7nAChR and NMDAR gene expression, and performance on a trace fear conditioning (TFC) task.
Results
KYNA levels were comparable between juvenile ECON and EKYN rats, whereas EKYN adults exhibited a ~3-fold increase in brain KYNA relative to ECONs. NR2A expression was persistently reduced (30–40 %) in EKYN rats at both ages. Compared to ECON adults, there was a 50 % reduction in NR1, and a trend toward decreased α7nAChR expression, in adult EKYN rats. Surprisingly, juvenile EKYN rats performed significantly
better
in the TFC paradigm than controls, whereas adult EKYN animals showed the predicted deficits.
Conclusions
Collectively, our results provide evidence that KP changes in the fetal brain alter neuronal development and cause age-dependent effects on neurochemistry and cognitive performance.
Levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine (±7nACh) and antagonist at glutamatergic N-methyl-D-aspartate (NMDA) receptors, are elevated in ...the brain of patients with schizophrenia (SZ). In rats, dietary exposure to KYNA’s immediate precursor kynurenine during the last week of gestation produces neurochemical and cognitive deficits in adulthood that resemble those seen in patients with SZ. The present experiments examined whether prenatal kynurenine exposure results in
age-dependent
changes in the kynurenine pathway (KP), expression of selected receptors, and cognitive function. Pregnant dams were fed unadulterated mash (progeny = ECON) or mash containing kynurenine (100 mg/day; progeny = EKYN) from embryonic day (ED) 15 to 22. Male offspring were assessed as juveniles, i.e. prior to puberty (postnatal day PD 32), or as adults (PD70) for brain KYNA levels, ±7nACh and NMDA receptor gene expression, and performance on a trace fear conditioning (TFC) task. KYNA levels were comparable between juvenile ECON and EKYN rats whereas EKYN adults exhibited a ~3-fold increase in brain KYNA relative to ECONs. NR2A expression was persistently reduced (30–40%) in EKYN rats at both ages. Compared to ECON adults, there was a 50% reduction in NR1, and a trend toward decreased ±7nACh expression, in adult EKYN rats. Surprisingly, juvenile EKYN rats performed significantly
better
in the TFC paradigm than controls, whereas adult EKYN animals showed the predicted deficits. Collectively, our results provide evidence that elevated KYNA in the fetal brain alters neuronal development and causes age-dependent effects on neurochemistry and cognitive performance.
Amyloid-β (Aβ) peptides derive from the amyloid precursor protein (APP) and play a pivotal role in Alzheimer's disease (AD) pathogenesis. Our previous work showed that the APP intracellular domain ...(AICD), which is produced simultaneously with Aβ, also contributes to the development of AD-like features. Studies show that administration of apolipoprotein E (apoE) and apoE-derived small peptide mimetics protect AD mouse models against these AD-like features. However, the effects of apoE-mimetic treatment on AICD-mediated AD-like pathologies remain to be elucidated.
To study the effects of an apoE mimetic (COG112) on neuroinflammation, hyperphosphorylation of tau and defects in adult neurogenesis in AICD- overexpressing transgenic mice (FeCγ25 line).
Beginning at 1 month of age, animals were administered subcutaneous COG112 3 times per week for 3 months, followed by immunohistochemical analysis for neuroinflammation, neurogenesis and phosphorylated tau.
Treatment with COG112 significantly reduced neuroinflammation in AICD mice and protected against impaired adult hippocampal neurogenesis. We also found that COG112 treatment reduced hyperphosphorylation and somatodendritic accumulation of tau in the hippocampus and cerebral cortex of AICD mice.
Reduction of neuroinflammation by the apoE-mimetic COG112 protects against impaired neurogenesis and tau pathology in AICD transgenic mice. These data suggest that neuroinflammation plays an important role in AICD-induced AD-like pathologies.
Cognitive deficits in executive functions such as attention and cognitive control form a core symptom cluster in schizophrenia that is most predicative of functional outcomes for patients, such as ...the ability to return to work. Unfortunately this class of symptoms is poorly treated with currently available neuroleptics and so far adjunctive treatment with potential pro-cognitive compounds has not yielded improvements in global cognition. Not only are alternative treatment strategies necessary, but there is a need for better validated preclinical tasks and animal models. The current work seeks to validate the rodent Target Detection Task (rTDT) and the embryonic kynurenine (EKYN) model as a platform for assessing the efficacy of cognitive training via prior experience in a cognitively demanding task. The central hypothesis guiding the experiments in this dissertation is that gestational elevations of kynurenine will induce a profile of translationally relevant attentional deficits in the rTDT and these deficits can be reversed with cognitive training. The first aim consisted of a validation of the rTDT. It was found that rTDT acquisition follows a stable and repeatable pattern. Additionally, rTDT performance is sensitive to manipulations of stimulus parameters including the reduction of stimulus duration and contrast. These manipulations result in predictable impairments in sensitivity, or the ability to discriminate between target and non-target stimuli. The rTDT was also shown to be sensitive to pharmacological challenges with agents that impair glutamatergic and cholinergic neurotransmission. These neurotransmitter systems are known to be essential for intact attentional processing. The second aim consisted of a validation of the EKYN model. EKYN animals, compared to control animals, showed disruptions of attentional processing and cognitive control. These deficits did not present during task acquisition but emerged upon challenge with task parameters that enhanced cognitive load in either the rTDT or the Maze Set Shifting task. EKYN animals were vulnerable to reductions in stimulus duration in the rTDT and vulnerable to extradimensional set shifts in the Maze Set Shifting task. The third aim consisted of a proof-of-concept for modeling cognitive training with prior experience in cognitively demanding tasks. To assess the generalization of the effect of cognitive training a fully crossed design was used with task order counterbalanced. EKYN rTDT training rescued deficits in cognitive flexibility in the EKYN animals. Interestingly this protective effect was specific to EKYN animals who were trained in the full rTDT compared to EKYN animals who were exposed to a simple reward-stimulus pairing. In contrast both EKYN maze trained and maze exposed animals showed a protective effect against the attentional deficits shown by EKYN animals in the rTDT. In conclusion the current work (1) further validates the rTDT as a translationally relevant task that challenges animals in the cognitive domains of attention, cognitive control and perception, (2) further validates the EKYN animal model as a naturalistic neurodevelopmental model that induces deficits in attentional processing and cognitive flexibility similar to the cognitive deficits present in patients with schizophrenia, (3) is the first to show, in a strongly validated animal model of schizophrenia, the efficacy of cognitive training in adulthood to reverse cognitive deficits.
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