Studies of neurons from human epilepsy tissue and comparable animal models of focal epilepsy have consistently reported a marked decrease in dendritic spine density on hippocampal and neocortical pyramidal cells. Spine loss is often accompanied by focal varicose swellings or beading of dendritic segments. An ongoing excitotoxic injury of dendrites (dendrotoxicity), produced by excessive release of glutamate during seizures, is often assumed to produce these abnormalities. Indeed, application of glutamate receptor agonists to dendrites can produce both spine loss and beading. However, the cellular mechanisms underlying the two processes appear to be different. One recent study suggests NMDA‐induced spine loss is produced by Ca2+‐mediated alterations of the spine cytoskeleton. In contrast, dendritic beading is not dependent on extracellular Ca2+; instead, it appears to be produced by the movement of Na+ and Cl− intracellularly and an obligate movement of water to maintain osmolarity. A decrease in dendritic spine density was recently reported in a model of recurrent focal seizures in early life. Unlike results from other models, dendritic beading was not observed, and other signs of neuronal injury and death were absent. Thus, additional mechanisms to those of excitotoxicity may produce dendritic spine loss in epileptic tissue. A hypothesis is presented that spine loss can be a product of a partial deafferentation of pyramidal cells, resulting from an activity‐dependent pruning of neuronal connectivity induced by recurring seizures. The dendritic abnormalities observed in epilepsy are commonly suggested to be a product and not a cause of epilepsy. However, anatomical remodeling may be accompanied by alterations in molecular expression and targeting of both voltage‐ and ligand‐gated channels in dendrites. It is conceivable that such changes could contribute to the neuronal hyperexcitability of epilepsy. Hippocampus 2000;10:617–625. © 2000 Wiley‐Liss, Inc.

Energy homeostasis involves central nervous system integration of afferent inputs that coordinately regulate food intake and energy expenditure. Here, we report that adult homozygous TNFalpha converting enzyme (TACE)-deficient mice exhibit one of the most dramatic examples of hypermetabolism yet reported in a rodent system. Because this effect is not matched by increased food intake, mice lacking TACE exhibit a lean phenotype. In the hypothalamus of these mice, neurons in the arcuate nucleus exhibit intact responses to reduced fat mass and low circulating leptin levels, suggesting that defects in other components of the energy homeostasis system explain the phenotype of Tace(DeltaZn/DeltaZn) mice. Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace(DeltaZn/DeltaZn) mice when compared with weight-matched controls suggest that deficient TACE activity is linked to increased sympathetic outflow. These findings collectively identify a novel and potentially important role for TACE in energy homeostasis.

March 11, 2008; doi:10.1152/ajpendo.00772.2007.-Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for patients with comorbid diabetes and depression. Clinical case studies in diabetic patients, however, suggest that SSRI therapy may exacerbate hypoglycemia. We hypothesized that SSRIs might increase the risk of hypoglycemia by impairing hormonal counterregulatory responses (CRR). We evaluated the effect of the SSRI sertraline on hormonal CRR to single or recurrent hypoglycemia in nondiabetic rats. Since there are time-dependent effects of SSRIs on serotonin neurotransmission that correspond with therapeutic action, we evaluated the effect of 6-or 20-day sertraline treatment on hypoglycemia CRR. We found that 6-day sertraline (SERT) treatment specifically enhanced the epinephrine response to a single bout of hypoglycemia vs. vehicle (VEH)-treated rats (t ϭ 120: VEH, 2,573 Ϯ 448 vs. SERT, 4,202 Ϯ 545 pg/ml, P Ͻ 0.05). In response to recurrent hypoglycemia, VEHtreated rats exhibited the expected impairment in epinephrine secretion (t ϭ 60: 678 Ϯ 73 pg/ml) vs. VEH-treated rats experiencing first-time hypoglycemia (t ϭ 60: 2,081 Ϯ 436 pg/ml, P Ͻ 0.01). SERT treatment prevented the impaired epinephrine response in recurrent hypoglycemic rats (t ϭ 60: 1,794 Ϯ 276 pgl/ml). In 20-day SERT-treated rats, epinephrine, norepinephrine, and glucagon CRR were all significantly elevated above VEH-treated controls in response to hypoglycemia. Similarly to 6-day SERT treatment, 20-day SERT treatment rescued the impaired epinephrine response in recurrent hypoglycemic rats. Our data demonstrate that neither 6-nor 20-day sertraline treatment impaired hormonal CRR to hypoglycemia in nondiabetic rats. Instead, sertraline treatment resulted in an enhancement of hypoglycemia CRR and prevented the impaired adrenomedullary response normally observed in recurrent hypoglycemic rats. epinephrine; adrenomedullary; hypoglycemia-associated autonomic failure INDIVIDUALS WITH DIABETES exhibit a twofold higher rate of depression compared with the general population (29). Comorbid depression and diabetes are associated with hyperglycemia and poor glycemic control (25), an accelerated progression of complications associated with diabetes (8, 26), and an increased risk of mortality (41). Selective serotonin reuptake inhibitors (SSRIs) are the drug of choice for the treatment of depression. The majority of clinical studies support the use of SSRIs in comorbid diabetes and depression (16,26,27). Diabetic patients on SSRI therapy can exhibit reduced fasting glucose levels, reduced body weight, improved glycemic control, and improved hemoglobin A 1c values compared with diabetic patients on other commonly prescribed antidepressants (15, 28). Furthermore, SSRI therapy effectively reduces depression recurrence in diabetic patients (27).Similarly to other antidepressant therapies (16), SSRIs can impact blood glucose levels; thus they can present potential risks to individuals with diabetes. Of particular significance, SSRI therapy in diab...

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Studies of neurons from human epilepsy tissue and comparable animal models of focal epilepsy have consistently reported a marked decrease in dendritic spine density on hippocampal and neocortical pyramidal cells. Spine loss is often accompanied by focal varicose swellings or beading of dendritic segments. An ongoing excitotoxic injury of dendrites (dendrotoxicity), produced by excessive release of glutamate during seizures, is often assumed to produce these abnormalities. Indeed, application of glutamate receptor agonists to dendrites can produce both spine loss and beading. However, the cellular mechanisms underlying the two processes appear to be different. One recent study suggests NMDA-induced spine loss is produced by Ca2+-mediated alterations of the spine cytoskeleton. In contrast, dendritic beading is not dependent on extracellular Ca2+; instead, it appears to be produced by the movement of Na+ and Cl- intracellularly and an obligate movement of water to maintain osmolarity. A decrease in dendritic spine density was recently reported in a model of recurrent focal seizures in early life. Unlike results from other models, dendritic beading was not observed, and other signs of neuronal injury and death were absent. Thus, additional mechanisms to those of excitotoxicity may produce dendritic spine loss in epileptic tissue. A hypothesis is presented that spine loss can be a product of a partial deafferentation of pyramidal cells, resulting from an activity-dependent pruning of neuronal connectivity induced by recurring seizures. The dendritic abnormalities observed in epilepsy are commonly suggested to be a product and not a cause of epilepsy. However, anatomical remodeling may be accompanied by alterations in molecular expression and targeting of both voltage- and ligand-gated channels in dendrites. It is conceivable that such changes could contribute to the neuronal hyperexcitability of epilepsy.