The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurons in chronic epilepsy. Discerning the mechanisms underlying signal integration within EC neurons is essential for understanding network excitability alterations involving the hippocampus during epilepsy. Twenty-four hours following a single seizure episode when there were no behavioral or electrographic seizures, we found enhanced spontaneous activity still present in the rat EC in vivo and in vitro. The increased excitability was accompanied by a profound reduction in I(h) in EC layer III neurons and a significant decline in HCN1 and HCN2 subunits that encode for h channels. Consequently, dendritic excitability was enhanced, resulting in increased neuronal firing despite hyperpolarized membrane potentials. The loss of I(h) and the increased neuronal excitability persisted for 1 week following seizures. Our results suggest that dendritic I(h) plays an important role in determining the excitability of EC layer III neurons and their associated neural networks.

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.

Eight adolescents (ages 13-18 years) who sustained traumatic brain injury (TBI) and eight gender- and age-matched typically developing (TD) adolescents underwent event-related functional MRI (fMRI) while performing a Sternberg letter recognition task. Encoding, maintenance, and retrieval were examined with memory loads of one or four items during imaging. Both groups performed above a 70% accuracy criterion and did not differ in performance. TD adolescents showed greater increase in frontal and parietal activation during high-load relative to low-load maintenance than the TBI group. The TBI patients showed greater increase in activation during high-load relative to low-load encoding and retrieval than the TD group. Results from this preliminary study suggest that the capability to differentially allocate neural resources according to memory load is disrupted by TBI for the maintenance subcomponent of working memory. The overrecruitment of frontal and extrafrontal regions during encoding and retrieval following TBI may represent a compensatory process.

Explosive blast is a frequent cause of traumatic brain injury (TBI) among personnel deployed to Afghanistan and Iraq. Functional magnetic resonance imaging (fMRI) with an event-related stimulus-response compatibility task was used to compare 15 subjects with mild, chronic blast-related TBI with 15 subjects who had not experienced a TBI or blast exposure during deployment. Six TBI subjects reported multiple injuries. Relative to the control group, TBI subjects had slightly slower responses during fMRI and increased somatic complaints and symptoms of post-traumatic stress disorder (PTSD) and depression. A between-group analysis indicated greater activation during stimulus-response incompatibility in TBI subjects within the anterior cingulate gyrus, medial frontal cortex, and posterior cerebral areas involved in visual and visual-spatial functions. This activation pattern was more extensive after statistically controlling for reaction time and symptoms of PTSD and depression. There was also a negative relationship between symptoms of PTSD and activation within posterior brain regions. These results provide evidence for increased task-related activation following mild, blast-related TBI and additional changes associated with emotional symptoms. Limitations of this study include no matching for combat exposure and different recruitment strategies so that the control group was largely a community-based sample, while many TBI subjects were seeking services.