A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains
Chakravarthi Narla, Tanner Scidmore, Jaymin Jeong, Michelle Everest, Peter Chidiac, Michael O. Poulter
Anxiety and stress increase the frequency of epileptic seizures. These behavioral states induce the secretion of corticotropin-releasing factor (CRF), a 40–amino acid neuropeptide neurotransmitter that coordinates many behavioral responses to stress in the central nervous system. In the piriform cortex, which is one of the most seizurogenic regions of the brain,CRFnormally dampens excitability. By contrast,CRF increased the excitability of the piriform cortex in rats subjected to kindling, a model of temporal lobe epilepsy. In nonkindled rats, CRF activates its receptor, a G protein (heterotrimeric guanosine triphosphate–binding protein)–coupled receptor, and signals through a Gaq/11-mediated pathway. After seizure induction, CRF signaling occurred through a pathway involving Gas. This change in signaling was associated with reduced abundance of regulator of G protein signaling protein type 2 (RGS2), which has been reported to inhibit Gas-dependent signaling. RGS2 knockout mice responded to CRF in a similar manner as epileptic rats. These observations indicate that seizures produce changes in neuronal signaling that can increase seizure occurrence by converting a beneficial stress response into an epileptic trigger.
CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury
Chakravarthi Narla, Paul S. Jung, Francisco Bautista Cruz, Michelle Everest, Julio Martinez-Trujillo and Michael O. Poulter
It is not known why there is increased risk to have seizures with increased anxiety and stress after traumatic brain injury (TBI). Stressors cause the release of corticotropin-releasing factor (CRF) both from the hypothalamic pituitary adrenal (HPA) axis and from CNS neurons located in the central amygdala and GABAergic interneurons. We have previously shown that CRF signaling is plastic, becoming excitatory instead of inhibitory after the kindling model of epilepsy. Here, using Sprague Dawley rats we have found that CRF signaling increased excitability after TBI. Following TBI, CRF type 1 receptor (CRFR1)-mediated activity caused abnormally large electrical responses in the amygdala, including fast ripples, which are considered to be epileptogenic. After TBI, we also found the ripple (120–250 Hz) and fast ripple activity (250 Hz) was cross-frequency coupled with (3–8 Hz) oscillations. CRFR1 antagonists reduced the incidence of phase coupling between ripples and fast ripples. Our observations indicate that pathophysiological signaling of the CRFR1 increases the incidence of epileptiform activity after TBI. The use for CRFR1 antagonist may be useful to reduce the severity and frequency of TBI associated epileptic seizures.
Neurobiology of Disease
The loss of interneuron functional diversity in the piriform cortex after induction of experimental epilepsy
Interneuronal functional diversity is thought to be an important factor in the control of neural network oscillations in many brain regions. Specifically, interneuron action potential firing patterns are thought to modulate brain rhythms. In neurological disorders such as epilepsy where brain rhythms are significantly disturbed interneuron function is largely unexplored. Thus the purpose of this study was to examine the functional diversity of piriform cortex interneurons (PC; an area of the brain that easily supports seizures) before and after kindling-induced epilepsy. Using cluster analysis, we found five control firing behaviors. These groups were termed: non-adapting very high frequency (NAvHF), adapting high frequency (AHF), adapting low frequency (ALF), strongly adapting low frequency (sALF), and weakly adapting low frequency (wALF).
Frontiers in Neural Circuits
Gain control of γ frequency activation by a novel feed forward disinhibitory loop: implications for normal and epileptic neural activity.
Zeinab Birjandian , Chakravarthi Narla and Michael O. Poulter
The inhibition of excitatory (pyramidal) neurons directly dampens their activity resulting in a suppression of neural network output. The inhibition of inhibitory cells is more complex. Inhibitory drive is known to gate neural network synchrony, but there is also a widely held view that it may augment excitability by reducing inhibitory cell activity, a process termed disinhibition. Surprisingly, however, disinhibition has never been demonstrated to be an important mechanism that augments or drives the activity of excitatory neurons in a functioning neural circuit. Using voltage sensitive dye imaging (VSDI) we show that 20–80 Hz stimulus trains, β–γ activation, of the olfactory cortex pyramidal cells in layer II leads to a subsequent reduction in inhibitory interneuron activity that augments the efficacy of the initial stimulus