The γ-aminobutyric acid (GABA) type A receptor (GABA A R) is the major inhibitory neurotransmitter receptor in the brain. Its multiple subunits show regional, developmental, and disease-related plasticity of expression; however, the regulatory networks controlling GABA A R subunit expression remain poorly understood. We report that the seizure-induced decrease in GABA A R α1 subunit expression associated with epilepsy is mediated by the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway regulated by brain-derived neurotrophic factor (BDNF). BDNF-and seizure-dependent phosphorylation of STAT3 cause the adenosine 3′,5′-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. JAK/STAT pathway inhibition prevents the seizure-induced decrease in GABA A R α1 abundance in vivo and, given that BDNF is known to increase the abundance of GABA A R α4 in a JAK/STATindependent manner, indicates that BDNF acts through at least two distinct pathways to influence GABA A R-dependent synaptic inhibition.

Altered function of ␥-aminobutyric acid type A receptors (GABA A Rs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by benzodiazepines) is related, in part, to changes in the mRNA levels of certain GABA A R subunits, including ␣4, and may play a role in epileptogenesis. The majority of GABA A Rs that contain ␣4 subunits are extra-synaptic due to lack of the ␥2 subunit and presence of ␦. However, it has been hypothesized that seizure activity may result in expression of synaptic receptors with altered properties driven by an increased pool of ␣4 subunits. Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant ␣4 subunit gene (GABRA4) expression after status epilepticus. We now report that brain derived neurotrophic factor (BDNF) is the endogenous signal that induces Egr3 expression via a PKC/MAPK-dependent pathway. Taken together with the fact that blockade of tyrosine kinase (Trk) neurotrophin receptors reduces basal GABRA4 promoter activity by 50%, our findings support a role for BDNF as the mediator of Egr3-induced GABRA4 regulation in developing neurons and epilepsy and, moreover, suggest that BDNF may alter inhibitory processing in the brain by regulating the balance between phasic and tonic inhibition.The type A ␥-aminobutyric acid (GABA) 5 receptor (GABA A R) is an integral ligand gated ion channel that mediates the majority of inhibition in the central nervous system. Being a hetero-oligomeric complex, it is composed of five membrane spanning subunits that are chosen from the products of 19 different genes (␣ 1-6 , ␤ 1-3 , ␥ 1-3 , ␦, ⑀, , 1-3 , and ). These genes are differentially transcribed during development and in various regions of the adult brain and spinal cord (1-5). Alteration in the function of GABA A Rs has been associated with a variety of diseases whose etiology leads to an imbalance between inhibition and excitation in specific populations of neurons (6 -8).For instance, changes in certain GABA A R subunit levels occur in dentate granule cells (DGCs) of both humans with temporal lobe epilepsy (TLE) and in animal models of TLE (6, 9). These molecular responses have been hypothesized to underlie persistent changes in GABA A R function associated with epileptogenesis. Most notably, individual DGCs display an elevation of ␣4 subunit mRNAs and a decrease in ␣1 (6). Receptors that contain ␣4 subunits have unique pharmacological properties that include heightened blockade of receptor function by zinc (11-13) and decreased benzodiazepine modulation (14). In addition, the majority of GABA A Rs that contain ␣4 subunits (co-assembled with a ␤ and ␦) are located extrasynaptically and mediate tonic GABA currents, while those containing ␣(1, 2, 3, or 5) without ␦ and with ␥2 are targeted to the synapse (1, 15). Although...

It is clear that brain‐derived neurotrophic factor (BDNF) plays a crucial role in organizing the response of the genome to dynamic changes in the extracellular environment that enable brain plasticity. BDNF has emerged as one of the most important signaling molecules for the developing nervous system as well as the impaired nervous system, and multiple diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, epilepsy, Rett’s syndrome, and psychiatric depression, are linked by their association with potential dysregulation of BDNF‐driven signal transduction programs. These programs are responsible for controlling the amount of activated transcription factors, such as cAMP response element binding protein, that coordinate the expression of multiple brain proteins, like ion channels and early growth response factors, whose job is to maintain the balance of excitation and inhibition in the nervous system. In this review, we will explore the evidence for BDNF's role in gene regulation side by side with its potential role in the etiology of neurological diseases. It is hoped that by bringing the datasets together in these diverse fields we can help develop the foundation for future studies aimed at understanding basic principles of gene regulation in the nervous system and how they can be harnessed to develop new therapeutic opportunities.

The regulated expression of type A ␥-aminobutyric acid (GABA) receptor (GABA A R) subunit genes plays a critical role in neuronal maturation and synaptogenesis. It is also associated with a variety of neurological diseases. Changes in GABA A receptor ␣1 subunit gene (GABRA1) expression have been reported in animal models of epilepsy, alcohol abuse, withdrawal, and stress. Understanding the genetic mechanism behind such changes in ␣ subunit expression will lead to a better understanding of the role that signal transduction plays in control over GABA A R function and brings with it the promise of providing new therapeutic tools for the prevention or cure of a variety of neurological disorders. Here we show that activation of protein kinase C increases ␣1 subunit levels via phosphorylation of CREB (pCREB) that is bound to the GABRA1 promoter (GABRA1p). In contrast, activation of protein kinase A decreases levels of ␣1 even in the presence of pCREB. Decrease of ␣1 is dependent upon the inducible cAMP early repressor (ICER) as directly demonstrated by ICER-induced down-regulation of endogenous ␣1-containing GABA A Rs at the cell surface of cortical neurons. Taken together with the fact that there are less ␣1␥2-containing GABA A Rs in neurons after protein kinase A stimulation and that activation of endogenous dopamine receptors down-regulates ␣1 subunit mRNA levels subsequent to induction of ICER, our studies identify a transcriptional mechanism for regulating the cell surface expression of ␣1-containing GABA A Rs that is dependent upon the formation of CREB heterodimers. ␥-Aminobutyric acid (GABA)4 type A receptors (GABA A Rs) are ligand-gated chloride ion channels that mediate the majority of fast synaptic inhibition in the mammalian brain (1). They are pentameric in structure and are composed of multiple subunit isoforms coming from eight distinct classes: ␣, ␤, ␥, ␦, , ⑀, , and . Diversity in receptor subtypes is controlled by the regulated expression of 19 different subunit genes and the alternative splicing of individual subunit transcripts (2-4). Most importantly, differential receptor subunit composition produces functionally and pharmacologically distinct GABA A Rs at certain times during development and in certain regions of the brain (5-8).The transcription of different GABA A R subunit genes (GABRs) is likely to involve a complex system of regulatory controls that remain to be identified. Several lines of evidence suggest that ␣1 subunit expression is activity-dependent (9 -11). Treatment with N-methyl-D-aspartate, a selective activator of an important class of excitatory ligand-gated ion channels, stimulates ␣1 subunit expression in cultured cerebellar granule cells (12, 13). In contrast, chronic treatment of cortical neurons with GABA decreases levels of GABA A R ␣1 subunit mRNAs (14 -16), which is dependent on voltage-gated calcium channel activity and most likely an alteration in transcription (15). In addition, prolonged benzodiazepine (BZ) treatment decreases ␣1 mRNA levels in the rat hippocampal CA...

Survival and differentiation of oligodendrocytes are important for the myelination of central nervous system (CNS) axons during development and crucial for myelin repair in CNS demyelinating diseases such as multiple sclerosis. Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. DR6 is expressed strongly in immature oligodendrocytes and weakly in mature myelin basic protein (MBP)-positive oligodendrocytes. Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. Treatment with a DR6 antagonist antibody promotes remyelination in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE) models. Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. These studies reveal a pivotal role for DR6 signaling in immature oligodendrocyte maturation and myelination that may provide new therapeutic avenues for the treatment of demyelination disorders such as multiple sclerosis.