Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis.

PURPOSE: Central nervous system plasticity is essential for normal function, but can also reinforce abnormal network behavior, leading to epilepsy and other disorders. The role of altered ion channel expression in abnormal plasticity has not been thoroughly investigated. Nav1.6 is the most abundantly expressed sodium channel in the nervous system. Because of its distribution in the cell body and axon initial segment, Nav1.6 is crucial for action potential generation. The goal of the present study was to investigate the possible role of changes in Nav1.6 expression in abnormal, activity-dependent plasticity of hippocampal circuits. METHODS: We studied kindling, a form of abnormal activity-dependent facilitation. We investigated: (1) sodium channel protein expression by immunocytochemistry and sodium channel messenger RNA (mRNA) by in situ hybridization, (2) sodium current by patch clamp recordings, and (3) rate of kindling by analysis of seizure behavior. The initiation, development, and expression of kindling in wild-type mice were compared to Nav1.6 +/-med(tg) mice, which have reduced expression of Nav1.6. RESULTS: We found that kindling was associated with increased expression of Nav1.6 protein and mRNA, which occurred selectively in hippocampal CA3 neurons. Hippocampal CA3 neurons also showed increased persistent sodium current in kindled animals compared to sham-kindled controls. Conversely, Nav1.6 +/-med(tg) mice resisted the initiation and development of kindling. DISCUSSION: These findings suggest an important mechanism for enhanced excitability, in which Nav1.6 may participate in a self-reinforcing cycle of activity-dependent facilitation in the hippocampus. This mechanism could contribute to both normal hippocampal function and to epilepsy and other common nervous system disorders.

Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory.

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.

Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function.

Neuropsychological and imaging studies indicate that attention deficit hyperactivity disorder (ADHD) is associated with alterations in prefrontal cortex (PFC) and its connections to striatum and cerebellum. Research in animals, in combination with observations of patients with cortical lesions, has shown that the PFC is critical for the regulation of behavior, attention, and affect using representational knowledge. The PFC is important for sustaining attention over a delay, inhibiting distraction, and dividing attention, while more posterior cortical areas are essential for perception and the allocation of attentional resources. The PFC in the right hemisphere is especially important for behavioral inhibition. Lesions to the PFC produce a profile of distractibility, forgetfulness, impulsivity, poor planning, and locomotor hyperactivity. The PFC is very sensitive to its neurochemical environment, and either too little (drowsiness) or too much (stress) catecholamine release in PFC weakens cognitive control of behavior and attention. Recent electrophysiological studies in animals suggest that norepinephrine enhances "signals" through postsynaptic alpha2A adrenoceptors in PFC, while dopamine decreases "noise" through modest levels of D1 receptor stimulation. alpha2A-Adrenoceptor stimulation strengthens the functional connectivity of PFC networks, while blockade of alpha2 receptors in the monkey PFC recreates the symptoms of ADHD, resulting in impaired working memory, increased impulsivity, and locomotor hyperactivity. Genetic alterations in catecholamine pathways may contribute to dysregulation of PFC circuits in this disorder. Medications may have many of their therapeutic effects by optimizing stimulation of alpha2A adrenoceptors and D1 receptors in the PFC, thus strengthening PFC regulation of behavior and attention.

A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia.

BACKGROUND: Neuroanatomic sexual dimorphisms have been correlated with behavioral differences between healthy men and women. We have reported higher orbitofrontal cortex to amygdala ratio (OAR) in women than men. Although gender differences in schizophrenia are evident clinically and correlate with neuroanatomic measures, their relationship to OAR has not been examined. METHODS: Magnetic resonance imaging was performed in 31 neuroleptic-naïve schizophrenic patients (16 men) and 80 healthy volunteers (34 men), aged less than 50 years. An automated tissue segmentation procedure was combined with expert-guided parcellation of orbitofrontal and amygdala volumes. RESULTS: Men with schizophrenia had increased OAR relative to healthy men, whereas women had decreased OAR. Increased OAR in men with schizophrenia reflected abnormally low amygdala volumes, whereas decreased OAR in women reflected abnormally low orbitofrontal volumes. Less severe negative symptoms were associated with increased OAR in men but with decreased OAR in women. In men, increased amygdala volume was associated with greater symptom severity, whereas in women higher volumes of both amygdala and orbitofrontal regions were associated with lesser severity of negative symptoms. CONCLUSIONS: These opposite OAR abnormalities, whereby men show feminization and women masculinization, suggest gender-mediated effects of the underlying neuropathologic processes. The correlations with symptom severity suggest that neuroanatomic abnormalities in OAR reflect compensatory brain changes.

Protein kinase C activity is associated with prefrontal cortical decline in aging.

Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.