Small molecules targeting Progranulin as potential therapeutics for Frontotemporal Dementia (FTD) and other dementias.

Background: Progranulin () plays a critical role in familial frontotemporal dementia (fFTD), where haploinsufficiency leads to reduction in PGRN levels in the brain, resulting in degeneration of neurons in the frontal lobe of brain responsible for personality, language, and behavior. FTD is the most common dementia in people under 60. Sortilin (), expressed by neurons, endocytoses, and delivers PGRN rapidly to lysosomes for degradation.

Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation.

Diazepam Accelerates GABAR Synaptic Exchange and Alters Intracellular Trafficking.

Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABARs). Here we define key molecular events impacting γ2 GABAR and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure and .

γ2 GABAR Trafficking and the Consequences of Human Genetic Variation.

GABA type A receptors (GABARs) mediate the majority of fast inhibitory neurotransmission in the central nervous system (CNS). Most prevalent as heteropentamers composed of two α, two β, and a γ2 subunit, these ligand-gated ionotropic chloride channels are capable of extensive genetic diversity (α1-6, β1-3, γ1-3, δ, 𝜀, 𝜃, π, ρ1-3). Part of this selective GABAR assembly arises from the critical role for γ2 in maintaining synaptic receptor localization and function.

Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway.

Ca/calmodulin-dependent protein kinase II (CaMKII) has long been implicated in neuronal injury caused by acute ischemia/reperfusion (I/R). However, its precise role and regulatory mechanisms remain obscure. Here, we investigated the role of the CaMKII family in neuronal survival during I/R.

Depolarizing, inhibitory GABA type A receptor activity regulates GABAergic synapse plasticity via ERK and BDNF signaling.

γ-aminobutyric acid (GABA) begins as the key excitatory neurotransmitter in newly forming circuits, with chloride efflux from GABA type A receptors (GABARs) producing membrane depolarization, which promotes calcium entry, dendritic outgrowth and synaptogenesis. As development proceeds, GABAergic signaling switches to inhibitory hyperpolarizing neurotransmission. Despite the evidence of impaired GABAergic neurotransmission in neurodevelopmental disorders, little is understood on how agonist-dependent GABAR activation controls the formation and plasticity of GABAergic synapses.

A versatile optical tool for studying synaptic GABA receptor trafficking.

Live-cell imaging methods can provide critical real-time receptor trafficking measurements. Here, we describe an optical tool to study synaptic γ-aminobutyric acid (GABA) type A receptor (GABAR) dynamics through adaptable fluorescent-tracking capabilities. A fluorogen-activating peptide (FAP) was genetically inserted into a GABAR γ2 subunit tagged with pH-sensitive green fluorescent protein (γ2FAP).

GABA type a receptor trafficking and the architecture of synaptic inhibition.

Ubiquitous expression of GABA type A receptors (GABA R) in the central nervous system establishes their central role in coordinating most aspects of neural function and development. Dysregulation of GABAergic neurotransmission manifests in a number of human health disorders and conditions that in certain cases can be alleviated by drugs targeting these receptors. Precise changes in the quantity or activity of GABA Rs localized at the cell surface and at GABAergic postsynaptic sites directly impact the strength of inhibition.

Retrotransposons Are the Major Contributors to the Expansion of the Muller F Element.

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in , but it is substantially larger (>18.