Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aß accumulation in mice.

Sleep disruptions promote increases of amyloid ß (Aß) and tau in the brain and increase Alzheimer's disease (AD) risk, but the precise mechanisms that give rise to sleep disturbances have yet to be defined. The thalamic reticular nucleus (TRN) is essential for sleep maintenance and for the regulation of slow-wave sleep (SWS). We examined the TRN in transgenic mice that express mutant human amyloid precursor protein (APP) and found reduced neuronal activity, increased sleep fragmentation, and decreased SWS time as compared to nontransgenic littermates. Selective activation of the TRN using excitatory DREADDs restored sleep maintenance, increased time in SWS, and reduced amyloid plaque load in both hippocampus and cortex. Our findings suggest that the TRN may play a major role in symptoms associated with AD. Enhancing TRN activity might be a promising therapeutic strategy for AD.

Corticothalamic network dysfunction and Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that is characterized by progressive cognitive decline and a prominent loss of hippocampal-dependent memory. Therefore, much focus has been placed on understanding the function and dysfunction of the hippocampus in AD. However, AD is also accompanied by a number of other debilitating cognitive and behavioral alterations including deficits in attention, cognitive processing, and sleep maintenance. The underlying mechanisms that give rise to impairments in such diverse behavioral domains are unknown, and identifying them would shed insight into the multifactorial nature of AD as well as reveal potential new therapeutic targets to improve overall function in AD. We present here several lines of evidence that suggest that dysregulation of the corticothalamic network may be a common denominator that contributes to the diverse cognitive and behavioral alterations in AD. First, we will review the mechanisms by which this network regulates processes that include attention, cognitive processing, learning and memory, and sleep maintenance. Then we will review how these behavioral and cognitive domains are altered in AD. We will also discuss how dysregulation of tightly regulated activity in the corticothalamic network can give rise to non-convulsive seizures and other forms of epileptiform activity that have also been documented in both AD patients and transgenic mouse models of AD. In summary, the corticothalamic network has the potential to be a master regulator of diverse cognitive and behavioral domains that are affected in AD.

Expression of class II histone deacetylases in two mouse models of temporal lobe epilepsy.

Epigenetic mechanisms like altered histone acetylation may have a crucial role in epileptogenesis. In two mouse models of temporal lobe epilepsy, we investigated changes in the expression of class II histone deacetylases (HDAC), a group of signal transducers that shuttle between nucleus and cytoplasm. Intrahippocampal injection of kainic acid (KA) induced a status epilepticus, development of spontaneous seizures (after 3 days), and finally chronic epilepsy and granule cell dispersion. Expression of class II HDAC mRNAs was investigated at different time intervals after KA injection in the granule cell layers and in sectors CA1 and CA3 contralateral to the site of KA injection lacking neurodegeneration. Increased expression of HDAC5 and 9 mRNAs coincided with pronounced granule cell dispersion in the KA-injected hippocampus at late intervals (14-28 days after KA) and equally affected both HDAC9 splice variants. In contrast, in the pilocarpine model (showing no granule cell dispersion), we observed decreases in the expression of HDAC5 and 9 at the same time intervals. Beyond this, striking similarities between both temporal lobe epilepsy models such as fast decreases in HDAC7 and 10 mRNAs during the acute status epilepticus were observed, notably also in the contralateral hippocampus not affected by neurodegeneration. The particular patterns of HDAC mRNA expression suggest a role in epileptogenesis and granule cell dispersion. Reduced expression of HDACs may result in increased expression of pro- and anticonvulsive proteins. On the other hand, export of HDACs from the nucleus into the cytoplasm could allow for deacetylation of cytoplasmatic proteins involved in axonal and dendritic remodeling, like granule cell dispersion. HDAC 5 and HDAC 9 expression is highly increased in granule cells of the KA-injected hippocampus and parallels granule cell dispersion. Both HDACs are thought to be targeted to the cytoplasm and to act there by deacetylating cytoplasmatic (e.g. cytosceleton-related) proteins.

Rapid changes in expression of class I and IV histone deacetylases during epileptogenesis in mouse models of temporal lobe epilepsy.

A prominent role of epigenetic mechanisms in manifestation of epilepsy has been proposed. Thus altered histone H3 and H4 acetylation has been demonstrated in experimental models of temporal lobe epilepsy (TLE). We now investigated changes in the expression of the class I and class IV histone deacetylases (HDAC) in two complementary mouse TLE models. Unilateral intrahippocampal injection of kainic acid (KA) induced a status epilepticus lasting 6 to 24h, development of spontaneous limbic seizures (2 to 3 days after KA injection) and chronic epilepsy, as revealed by telemetric recordings of the EEGs. Mice were killed at different intervals after KA injection and expression of HDAC mRNAs was investigated by in situ hybridization. We observed marked decreases in the expression of HDACs 1, 2 and 11 (by up to 75%) in the granule cell and pyramidal cell layers of the hippocampus during the acute status epilepticus (2 to 6h after KA injection). This was followed by increased expression of all class I HDAC mRNAs in all principal cell layers of the hippocampus after 12 to 48 h. In the chronic phase, 14 and 28 days after KA, only modest increases in the expression of HDAC1 mRNA were observed in granule and pyramidal cells. Immunohistochemistry using an antibody detecting HDAC2 revealed results consistent with the mRNA data and indicates also expression in glial cells on the injection side. Similar changes as seen in the KA model were observed after a pilocarpine-induced status epilepticus except that decreases in HDACs 2, 3 and 8 were also seen at the chronic 28 day interval. The prominent decreases in HDAC expression during status epilepticus are consistent with the previously demonstrated increased expression of numerous proteins and with the augmented acetylation of histone H4. It is suggested that respective putative gene products could facilitate proconvulsive as well as anticonvulsive mechanisms. The increased expression of all class I HDACs during the "silent phase", on the other hand, may be related to decreased histone acetylation, which could cause a decrease in expression of certain proteins, a mechanism that could also promote epileptogenesis. Thus, addressing HDAC expression may have a therapeutic potential in interfering with a status epilepticus and with the manifestation of TLE.