Ketamine Induced Deficits in Working Memory with Relevance to Schizophrenia

Schizophrenia is a chronic debilitating brain disorder, which affects approximately one per­cent of the adult population worldwide. The symptoms of schizophrenia are commonly divided into three broad classes: positive symptoms, negative symptoms, and cognitive disturbances (Kay, et al., 1987). The positive symptoms of schizophrenia include hallucinations, delusions, and dis­organized thinking, while the negative symptoms include affective flattening, social withdrawal, and an inability to plan and carry out future activities. The cognitive disturbances exhibited in schizophrenia include deficits in spatial reference and working memory as well as difficulties with focus and attention (Lewis et. al., 2007). Several models have been proposed as to the etiology of schizophrenia, one of which proposes the hypofunction of a discrete class of excitatory receptors (NMDA) on primarily inhibitory circuits in the brain. This change in signaling is argued to give rise to a loss of coordinated network activity throughout the brain resulting in deficits observed in schizophrenia (Figure 1). Data for this model is based on postmortem alterations in inhibitory cir­cuits and the ability of drugs that block the function of the NMDA receptor (NMDA antagonists) to produce deficits similar to those seen in schizophrenia populations (Coyle, 2012). The ability of these NMDA antagonists to produce psychosis similar to what is observed in schizophrenia has led to their extensive use in studying the mechanisms responsible for the disorder. Previous studies in our laboratory have demonstrated the ability of ketamine, an NMDA receptor antago­nist, to produce deficits in rodent’s spatial and emotional learning and memory consistent with observations in schizophrenia populations (Bolton et al., 2012; Sabbagh et al., 2012). In these investigations, it was also shown that ketamine administration was sufficient to induce alterations in inhibitory circuits in the brain that are commonly implicated in schizophrenia (Sabbagh et al., 2013). In the present study, we examined the extent to which the same administration of ketamine produced deficits in rodent’s spatial reference and working memory performance in the radial arm maze task. As working memory deficits are a core pathological feature of schizophrenia, these in­vestigations seek to further the validity of the ketamine model as it relates to the etiological origin of schizophrenia

Modulatory Effects of GABA(B) Receptor Facilitation in a Model of Chronic Inflammation

Inflammation within the brain (neuroinflammation) has been associated with a number of neurodegenerative diseases, including Alzheimerʼs disease (AD) (Solito et al., 2012). Within the brain, inflammation is defined broadly as prolonged activation of the brainʼs immune cells, known as glial cells. Excessive activation of glial cells within the brains of AD patients is a hallmark of the disease, however the mechanism by which this contributes to disease pathology is relatively unclear (Jo et al., 2014). Recently, studies have shown that glial cells, known as astrocytes, are able to synthesize and release the inhibitory neurotransmitter GABA (Charles et al., 2003). Further, microglia cells, the primary immunocompetent cells of the brain, have been shown to be GABAceptive cells, which express GABA (B) type receptors (Kuhn et al., 2004). Early characterizations of AD first described alterations in astrocyte location and activation in the disease and interestingly, differences in the total abundance of GABA within the brains of AD patients have recently been reported. Combined, these data provide support for the hypothesis that astrocytes regulate microglia activity through the release of GABA acting at GABA(B) type receptors. The activation of GABA(B) on microglia may serve to reduce the activation status of these microglia, thereby reducing the number of pro-inflammatory cytokines present within the brain (Streit et al., 2002). In the present study, we examined the effects of the GABA(B) agonist baclofen on chronic inflammation in rodents administered lipopolysaccharide (LPS). LPS is a bacterial endotoxin derived from the cell wall of gram-negative bacteria and is capable of mounting an immune response through the activation of toll-like receptor 4 (TLR4). Our data indicate that the administration of baclofen initially attenuated the pyrogenic effects of LPS administration, though this effect was lost after two weeks of injections. The administration of baclofen also rescued deficits in spatial learning and memory seen in animals chronically administered LPS. Furthermore, a significant increase in the total abundance of AB oligomers, believed to play a role in the pathology of AD, was seen in the brains of animals chronically administered LPS. Together, these data provide evidence that the modulation of GABA(B) receptor function altered the immune response evoked by activation of TLR4. These data also provide support for a potential role of GABA(B) in modulating aberrant immune activity seen in AD populations

McNair Research Journal - Summer 2015

Journal articles based on research conducted by undergraduate students in the McNair Scholars Program Table of Contents Biography of Dr. Ronald E. McNair Statements: Dr. Neal J. Smatresk, UNLV President Dr. Juanita P. Fain, Vice President of Student Affairs Dr. William W. Sullivan, Associate Vice President for Retention and Outreach Mr. Keith Rogers, Deputy Executive Director of the Center for Academic Enrichment and Outreach McNair Scholars Institute Staf