Cognitive Function in BK Channel Knock-Out Mice

BK channels are large conductance potassium channels activated by both Ca2+ concentration and membrane depolarization. They recently have been implicated to be involved in sensorimotor gating and higher cognitive function. However, it is not yet clear to what extent these channels affect these functions. The purpose of this study is to assess the role of BK channels in sensorimotor gating and cognitive function. We used a C57BL6 and SV129 hybrid mouse model in which the pore forming alpha subunit was genetically deleted. We employed the acoustic startle response to assess mechanisms of sensory gating (habituation and PPI), and the Y-maze and Morris water maze to test higher cognitive function. We found that BK channel knock-out mice had impaired sensorimotor gating as well as deficits in spatial learning; however their working and spatial reference memory was intact. Thus BK channels seemingly have a crucial role in basic and higher cognitive function

Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory

Genetic variations in the large-conductance, voltage- and calcium activated potassium channels (BK channels) have been recently implicated in mental retardation, autism and schizophrenia which all come along with severe cognitive impairments. In the present study we investigate the effects of functional BK channel deletion on cognition using a genetic mouse model with a knock-out of the gene for the pore forming α-subunit of the channel. We tested the F1 generation of a hybrid SV129/C57BL6 mouse line in which the slo1 gene was deleted in both parent strains. We first evaluated hearing and motor function to establish the suitability of this model for cognitive testing. Auditory brain stem responses to click stimuli showed no threshold differences between knockout mice and their wild-type littermates. Despite of muscular tremor, reduced grip force, and impaired gait, knockout mice exhibited normal locomotion. These findings allowed for testing of sensorimotor gating using the acoustic startle reflex, as well as of working memory, spatial learning and memory in the Y-maze and the Morris water maze, respectively. Prepulse inhibition on the first day of testing was normal, but the knockout mice did not improve over the days of testing as their wild-type littermates did. Spontaneous alternation in the y-maze was normal as well, suggesting that the BK channel knock-out does not impair working memory. In the Morris water maze knock-out mice showed significantly slower acquisition of the task, but normal memory once the task was learned. Thus, we propose a crucial role of the BK channels in learning, but not in memory storage or recollection

Habituation of reflexive and motivated behavior in mice with deficient BK channel function.

Habituation is considered the most basic form of learning. It describes the decrease of a behavioral response to a repeated non-threatening sensory stimulus and therefore provides an important sensory filtering mechanism. While some neuronal pathways mediating habituation are well described, underlying cellular/molecular mechanisms are not yet fully understood. In general, there is an agreement that short-term and long-term habituation are based on different mechanisms. Historically, a distinction has also been made between habituation of motivated versus reflexive behavior. In recent studies in invertebrates the large conductance voltage- and calcium-activated potassium (BK) channel has been implicated to be a key player in habituation by regulating synaptic transmission. Here, we tested mice deficient for the pore forming α-subunit of the BK channel for short-term and long-term habituation of the acoustic startle reflex (reflexive behavior) and of the exploratory locomotor behavior in the open field box (motivated behavior). Short-term habituation of startle was completely abolished in the BK knock-out mice, whereas neither long-term habituation of startle nor habituation of motivated behavior was affected by the BK deficiency. Our results support a highly preserved mechanism for short-term habituation of startle across species that is distinct from long-term habituation mechanisms. It also supports the notion that there are different mechanisms underlying habituation of motivated behavior versus reflexive behavior

Opioids and cerebral physiology in the acute management of traumatic brain injury: a systematic review

Background: Following traumatic brain injury (TBI), optimization of cerebral physiology is recommended to promote more favourable patient outcomes. Accompanying pain and agitation are commonly treated with sedative and analgesic agents, such as opioids. However, the impact of opioids on certain aspects of cerebral physiology is not well established. Objective: To conduct a systematic review of the evidence on the effect of opioids on cerebral physiology in TBI during acute care. Methods: A comprehensive literature search was conducted in five electronic databases for articles published in English up to November 2017. Studies were included if: (1) the study sample was human subjects with TBI; (2) the sample size was ≥3; (3) subjects were given an opioid during acute care; and (4) any measure of cerebral physiology was evaluated. Cerebral physiology measures were intracranial pressure (ICP), cerebral perfusion pressure (CPP), and mean arterial pressure (MAP). Subject and study characteristics, treatment protocol, and results were extracted from included studies. Randomized controlled trials were evaluated for methodological quality using the Physiotherapy Evidence Database tool. Levels of evidence were assigned using a modified Sackett scale. Results: In total, 22 studies met inclusion criteria, from which six different opioids were identified: morphine, fentanyl, sufentanil, remifentanil, alfentanil, and phenoperidine. The evidence for individual opioids demonstrated equally either: (1) no effect on ICP, CPP, or MAP; or (2) an increase in ICP with associated decreases in CPP and MAP. In general, opioids administered by infusion resulted in the former outcome, whereas those given in bolus form resulted in the latter. There were no significant differences when comparing different opioids, with the exception of one study that found fentanyl was associated with lower ICP and CPP than morphine and sufentanil. There were no consistent results when comparing opioids to other non-opioid medications. Conclusion: Several studies have assessed the effect of opioids on cerebral physiology during the acute management of TBI, but there is considerable heterogeneity in terms of study methodology and findings. Opioids are beneficial in terms of analgesia and sedation, but bolus administration should be avoided to prevent additional or prolonged unfavourable alterations in cerebral physiology. Future studies should better elucidate the effects of different opioids as well as varying dosages in order to develop improved understanding as well as allow for tighter control of cerebral physiology

Habituation of reflexive and motivated behaviour in mice with deficient BK channel function

Habituation is considered the most basic form of learning. It describes the decrease of a behavioral response to a repeated non-threatening sensory stimulus and therefore provides an important sensory filtering mechanism. While some neuronal pathways mediating habituation are well described, underlying cellular/molecular mechanisms are not yet fully understood. In general, there is an agreement that short-term and long-term habituation are based on different mechanisms. Historically, a distinction has also been made between habituation of motivated versus reflexive behavior. In recent studies in invertebrates the large conductance voltage- and calcium-activated potassium (BK) channel has been implicated to be a key player in habituation by regulating synaptic transmission. Here, we tested mice deficient for the pore forming α-subunit of the BK channel for short-term and long-term habituation of the acoustic startle reflex (reflexive behavior) and of the exploratory locomotor behavior in the open field box (motivated behavior). Short-term habituation of startle was completely abolished in the BK knock-out mice, whereas neither long-term habituation of startle nor habituation of motivated behavior was affected by the BK deficiency. Our results support a highly preserved mechanism for short-term habituation of startle across species that is distinct from long-term habituation mechanisms. It also supports the notion that there are different mechanisms underlying habituation of motivated behavior versus reflexive behavior

Spatial learning and memory in the Morris water maze.

<p>(<b>A</b>) The average escape latency improved across the training trails in all genotypes, but especially on days one to three, the BKα^−/− mice improve less within the training sessions. Note that on the last training trail on day 4 they caught up and performed as well as the WT mice. (<b>B</b>) Escape latency as a function of days of experience with the task. The average escape latency for each day was fitted with a one component exponential function for each genotype and time constants were derived from the resulting functions. The BKα^−/− mice have a longer time constant then the WT and the BKα^+/− mice. (<b>C</b>) Performance on the probe day. All mice spend a significant higher amount of time in the quadrant where previously the platform was hidden (target, solid dark grey) than in any other quadrant. The dashed line indicates 25% chance criterion.</p

Prepulse inhibition (PPI) of the acoustic startle response.

<p>(<b>A</b>) On the first day of testing no significant differences in prepulse inhibition were found between genotypes for all tested inter-stimulus intervals. (<b>B</b>) Across days the WT and BKα^+/− mice showed improvement in PPI whereas the BKα^−/− mice did not. The average PPI for all tested ISI is shown, since no effect of ISI was reported by the repeated measurements ANOVA. The right panel shows the average difference in PPI between the fifth and first day of testing. Differences were calculated for each single animal and then averaged for genotypes.</p

Locomotion.

<p>(<b>A</b>) BKα^−/− mice show normal locomotion in the open field box as well as (<b>B</b>) normal rearing activity.</p