The central and peripheral components of the nervous system exhibit extensive integration and interaction with the immune system in both health and disease. Components of the adaptive immune system touch all systems in the body through the blood and lymphatic vascular system, as was described in the chapter on immunobiology in Part I of this book. The nervous system is no exception to adaptive immune system interface. The immunobiology described in this chapter focuses on features of the innate and adaptive immune systems which are specific to the nervous system, and which are especially critical to health and diseases of the central nervous system. Selected immune conditions of the nervous system are explored in more detail to examine the complex interactions of the immune system with the nervous system and the consequences of imbalance between these systems on human health.

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.

The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha7 nicotinic acetylcholine receptors (alpha 7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain MYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56 -80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the alpha 7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11-14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set-shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ. (C) 2014 Elsevier Ltd. All rights reserved.

Cognitive deficits represent a core symptom cluster in schizophrenia that are thought to reflect developmental dysregulations within a neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), and prefrontal cortex (PFC). The present experiments determined the cognitive effects of transiently inactivating VH in rats during a sensitive period of development. Neonatal (postnatal day 7, PD7) and adolescent (PD32) male rats received a single bilateral infusion of saline or tetrodotoxin (TTX) within the VH to transiently inactivate local circuitry and efferent outflow. Rats were tested as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire the first reversal and extra-dimensional shift (ED) stages. These impairments were age and region-specific as rats infused with TTX into the VH at PD32, or into the dorsal hippocampus at PD7, exhibited performance in the task similar to that of controls. Finally, acute systemic administration of the partial α7 nicotinic acetylcholine receptor (nAChR) agonist SSR 180711 (3.0 mg/kg) eliminated the TTX-induced performance deficits. Given that patients with schizophrenia exhibit hippocampal pathophysiology and deficits in the ED stages of set-shifting tasks, our results support the significance of transient hippocampal inactivation as an animal model for studying the cognitive impairments in schizophrenia as well as the pro-cognitive therapeutic potential of α7 nAChR agonists.