Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases.

Severe dynein dysfunction in cholinergic neurons exacerbates ALS-like phenotypes in a new mouse model.

Cytoplasmic dynein 1, a motor protein essential for retrograde axonal transport, is increasingly implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this study, we developed a novel mouse model that combines the Legs at odd angles (Loa, F580Y) point mutation in the dynein heavy chain with a cholinergic neuron-specific knockout of the dynein heavy chain. This model, for the first time, allows us to investigate the impact of Loa allele exclusivity in these neurons into adulthood.

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects.

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss.

Morphological and functional correlates of vestibular synaptic deafferentation and repair in a mouse model of acute-onset vertigo.

Damage to cochlear primary afferent synapses has been shown to be a key factor in various auditory pathologies. Similarly, the selective lesioning of primary vestibular synapses might be an underlying cause of peripheral vestibulopathies that cause vertigo and dizziness, for which the pathophysiology is currently unknown. To thoroughly address this possibility, we selectively damaged the synaptic contacts between hair cells and primary vestibular neurons in mice through the transtympanic administration of a glutamate receptor agonist.

Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator.

Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers.

Reduced Balance Restoration Capacities Following Unilateral Vestibular Insult in Elderly Mice.

Acute vestibular syndrome (AVS) is characterized by severe posturo-locomotor and vestibulo-oculomotor impairment and accompanies several types of peripheral vestibulopathies (PVP). We know very little about its etiology, how its various symptoms are expressed and how it evolves with age. Robust repair capabilities of primary vestibular synapses have recently been shown to restore behavioral functionality.

Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction.

Although the elaborate combination of histone and non-histone protein complexes defines chromatin organization and hence regulates numerous nuclear processes, the role of chromatin organizing proteins remains unexplored at the organismal level. The highly abundant, multifunctional, chromatin-associated protein and transcriptional coactivator positive coactivator 4 (PC4/Sub1) is absolutely critical for life, because its absence leads to embryonic lethality. Here, we report results obtained with conditional PC4 knock-out (PC4(f/f) Nestin-Cre) mice where PC4 is knocked out specifically in the brain.

Dorsal hippocampus and medial prefrontal cortex each contribute to the retrieval of a recent spatial memory in rats.

Systems-level consolidation models propose that recent memories are initially hippocampus-dependent. When remote, they are partially or completely dependent upon the medial prefrontal cortex (mPFC). An implication of the mPFC in recent memory, however, is still debated.

Acetyltransferases (HATs) as targets for neurological therapeutics.

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen long-term events in the brain circuitry (e.g.

A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice.

Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small-molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex.

The ventral midline thalamus contributes to strategy shifting in a memory task requiring both prefrontal cortical and hippocampal functions.

Electrophysiological and neuroanatomical evidence for reciprocal connections with the medial prefrontal cortex (mPFC) and the hippocampus make the reuniens and rhomboid (ReRh) thalamic nuclei a putatively major functional link for regulations of cortico-hippocampal interactions. In a first experiment using a new water escape device for rodents, the double-H maze, we demonstrated in rats that a bilateral muscimol (MSCI) inactivation (0.70 vs 0.

The match/mismatch of visuo-spatial cues between acquisition and retrieval contexts influences the expression of response vs. place memory in rats.

Animals can perform goal-directed tasks by using response cues or place cues. The underlying memory systems are occasionally presented as competing. Using the double-H maze test (Pol-Bodetto et al.