Cannabinoid regulation of neurons in the dentate gyrus during epileptogenesis: Role of CB1R-associated proteins and downstream pathways.

The hippocampal formation plays a central role in the development of temporal lobe epilepsy (TLE), a disease characterized by recurrent, unprovoked epileptic discharges. TLE is a neurologic disorder characterized by acute long-lasting seizures (i.e., abnormal electrical activity in the brain) or seizures that occur in close proximity without recovery, typically after a brain injury or status epilepticus. After status epilepticus, epileptogenic hyperexcitability develops gradually over the following months to years, resulting in the emergence of chronic, recurrent seizures. Acting as a filter or gate, the hippocampal dentate gyrus (DG) normally prevents excessive excitation from propagating through the hippocampus, and is considered a critical region in the progression of epileptogenesis in pathological conditions. Importantly, lipid-derived endogenous cannabinoids (endocannabinoids), which are produced on demand as retrograde messengers, are central regulators of neuronal activity in the DG circuit. In this review, we summarize recent findings concerning the role of the DG in controlling hyperexcitability and propose how DG regulation by cannabinoids (CBs) could provide avenues for therapeutic interventions. We also highlight possible pathways and manipulations that could be relevant for the control of hyperexcitation. The use of CB compounds to treat epilepsies is controversial, as anecdotal evidence is not always validated by clinical trials. Recent publications shed light on the importance of the DG as a region regulating incoming hippocampal excitability during epileptogenesis. We review recent findings concerning the modulation of the hippocampal DG circuitry by CBs and discuss putative underlying pathways. A better understanding of the mechanisms by which CBs exert their action during seizures may be useful to improve therapies.

Dendritic hold and read: a gated mechanism for short term information storage and retrieval.

Two contrasting theories have been proposed to explain the mechanistic basis of short term memory. One theory posits that short term memory is represented by persistent neural activity supported by reverberating feedback networks. An alternate, more recent theory posits that short term memory can be supported by feedforward networks. While feedback driven memory can be implemented by well described mechanisms of synaptic plasticity, little is known of possible molecular and cellular mechanisms that can implement feedforward driven memory. Here we report such a mechanism in which the memory trace exists in the form of glutamate-bound but Mg(2+)-blocked NMDA receptors on the thin terminal dendrites of CA1 pyramidal neurons. Because glutamate dissociates from subsets of NMDA receptors very slowly, excitatory synaptic transmission can leave a silent residual trace that outlasts the electrical activity by hundreds of milliseconds. Read-out of the memory trace is possible if a critical level of these bound-but-blocked receptors accumulates on a dendritic branch that will allow these quasi-stable receptors to sustain a regenerative depolarization when triggered by an independent gating signal. This process is referred to here as dendritic hold and read (DHR). Because the read-out of the input is not dependent on repetition of the input and information flows in a single-pass manner, DHR can potentially support a feedforward memory architecture.

Gestational toluene exposure effects on spontaneous and amphetamine-induced locomotor behavior in rats.

Gestational Toluene Exposure Effects on Spontaneous and Amphetamine-Induced Locomotor Behavior in Rats. Bowen, S.E., Mohammadi, M.H., Batis, J.C., and Hannigan, J.H. Neurotoxicology and Teratology, XX, 2006. The abuse of volatile organic solvents (inhalants) continues to be a major health concern throughout the world. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. The neurobehavioral teratogenic sequelae of solvent abuse (i.e., repeated, brief inhalation exposures to very high concentrations of solvents) have not been examined thoroughly. In a preclinical model of inhalant abuse, timed-pregnant Sprague-Dawley rats were exposed to 0, 8000, or 12,000 parts per million (ppm) for 15 min twice daily from gestation day 8 (GD8) through GD20. In the first experiment, separate groups of offspring were observed individually in an open-field on postnatal day 22 (PN22), PN42 or PN63. In the second experiment, other offspring given identical prenatal toluene exposures were observed in an "open-field" following an acute i.p. injection of amphetamine (0, 0.56, 1.78 mg/kg) on PN28. Automated measurements of distance traveled and ambulatory time were recorded. Prenatal toluene exposure resulted in small alterations in spontaneous activity compared to non-exposed rats. Prenatal exposure to 12,000 ppm toluene resulted in significant hyposensitivity to the locomotor stimulatory effects of the amphetamine challenge in male but not female rats on PN28. The results demonstrate that prenatal exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous and amphetamine-induced locomotor behavior in rats. The expression of these effects also appears to depend upon the postnatal age of testing. These results imply that abuse of organic solvents during pregnancy in humans may also produce long-lasting effects on biobehavioral development.

Abuse pattern of gestational toluene exposure and early postnatal development in rats.

Inhalant abuse in the United States trails only alcohol, marijuana and nicotine abuse. Toluene, found in glues and cleaners, is among the most commonly abused inhalants. While teratogenicity due to occupational exposure to organic solvents (i.e., relatively long-term exposure to lower concentrations) has been studied, the teratogenic potential of organic solvent abuse (i.e., brief inhalation exposures to very high concentrations) has not been thoroughly examined. In a preclinical model of abuse patterns of fetal solvent exposure, timed-pregnant rats were exposed to 8000 parts per million (ppm) or 12,000 ppm of toluene, or to air (0 ppm), for 15 min twice daily from gestation day 8 (GD8) through GD20. After parturition, pups were tested from postnatal day 4 (PN4) to PN21 in a developmental test battery including measures of growth (i.e., body weight), maturational milestones (i.e., pinnae unfolding, incisor eruption and eye opening) and biobehavioral development (e.g., negative geotaxis, surface righting and grip strength). Pups exposed in utero to 12,000 ppm toluene weighed significantly less than the control pups at all ages before PN16. There were significant toluene-induced increases in an index of poor perinatal outcome (i.e., a combination of malformations, "runting" and neonatal death) and deficits in negative geotaxis. There were no significant delays in reaching maturational milestones. The results demonstrate that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth restriction, malformation and impairments of biobehavioral development in rats. A comparison of the present outcomes to previous studies of occupational exposure patterns suggests that for a given daily "dose" of toluene, a binge pattern of exposure may pose a greater risk for fetal development. Since the pattern of exposure in this experiment models binge exposure in human solvent abuse, the results imply that abuse of inhaled organic solvents, such as toluene, can cause similar teratogenic outcomes in humans.