Nicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory: Behavioral and electrophysiological studies.

Nicotine alleviates cognitive impairment associated with a variety of health conditions. We examined the effect of chronic nicotine treatment on adult-onset hypothyroidism-induced impairment of learning and memory in rats. Hypothyroidism was induced by surgical removal of thyroid glands (thyroidectomy). One month later, chronic nicotine treatment (1 mg/kg sc, twice/day) was instituted for 4-6 weeks. Test of hippocampus-dependent spatial learning and memory in the radial arm water maze showed that hypothyroidism impaired learning as well as short-term and long-term memory retention. Chronic nicotine treatment reversed the hypothyroidism-induced learning and memory impairment. In normal rats, chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anesthetized hypothyroid rats showed severe reduction of both early-phase and late-phase long-term potentiation (LTP) magnitude, which was reversed in nicotine-treated hypothyroid rats. These results show that chronic nicotine treatment prevents hypothyroidism-induced impairment of spatial cognition and LTP.

Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF.

Electrophysiological recording reveals that chronic nicotine treatment prevents stress-induced impairment of long-term potentiation (LTP) in the CA1 region of the hippocampus of anesthetized rats. We investigated the molecular mechanism of this action of nicotine in the CA1 region. Immunoblot analysis showed that chronic nicotine treatment (1 mg/kg, 2 times/day) normalized the stress-induced decrease in the basal levels of BDNF, CaMKII (total and phosphorylated; P-CaMKII), and calmodulin. Additionally, nicotine reversed the stress-induced increase in calcineurin basal levels. Chronic nicotine treatment also markedly increased the basal levels of BDNF in naïve rats. Furthermore, high-frequency stimulation (HFS), which increased the levels of P-CaMKII in control as well as nicotine-treated stressed rats, failed to increase P-CaMKII levels in untreated stressed rats. Compared to unstimulated control, the levels of both total CaMKII and calcineurin were increased after HFS in all groups including the stressed, but no changes were detected after HFS in the levels of BDNF and calmodulin. These results indicate that normalization by nicotine of the stress-induced changes in the levels of signaling molecules including BDNF may contribute to the recovery of LTP.

Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies.

Hypothyroidism impairs synaptic plasticity as well as learning and memory. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. Recently, we have shown that hypothyroidism impairs LTP and cognition in adult rats. We have studied the effect of thyroxin replacement therapy on hypothyroidism-induced LTP impairment using electrophysiological and molecular approaches. Recording from CA1 region of the hippocampus in anesthetized adult rat indicated that 6 weeks of thyroxin replacement therapy (20 microg/kg/day) fully restored LTP impaired by hypothyroidism. Western blotting showed reduction in phosphorylated (P)-CAMKII, total-CaMKII, neurogranin, and calmodulin basal levels in the CA1 region of the hippocampus of hypothyroid rats. The levels of these molecules were normalized by thyroxin replacement therapy. The hypothyroid-induced elevation of basal calcineurin levels and activity was also normalized by thyroxin treatment. However, thyroxin replacement therapy did not restore hypothyroidism-induced reduction in PKCgamma basal protein levels. Additionally, real-time PCR, showed a reduction in basal neurogranin mRNA level that was normalized by thyroxin replacement therapy. In the sham (control) rats, induction of LTP by high-frequency stimulation increases P-CaMKII, and total CaMKII levels as well as CaMKII phosphotransferase activity. However, in hypothyroid rats, the same stimulation protocol induced an increase only in total-CaMKII. Thyroxin treatment normalized the levels and activity of these molecules. The results demonstrated that thyroxin therapy normalized the electrophysiological and molecular effects of hypothyroidism on the CA1 region and emphasized the critical role P-CaMKII plays in hypothyroidism-induced LTP impairment.

Role of phosphorylated CaMKII and calcineurin in the differential effect of hypothyroidism on LTP of CA1 and dentate gyrus.

Hypothyroidism impairs early long-term potentiation (LTP) in the CA1 but not in the dentate gyrus (DG) of hippocampus of anesthetized adult rats. Protein levels and activities of signaling molecules in both the CA1 and DG of surgically thyroidectomized and sham-operated euthyroid rats were measured. Basal levels of total calmodulin kinase II (CaMKII) protein in both the CA1 and DG were decreased in hypothyroidism. Marked reduction of basal P-CaMKII levels and CaMKII activity was seen in CA1, but not in the DG of the same hypothyroid animals. Basal levels of calmodulin and protein kinase Cgamma (PKCgamma) were decreased in CA1 but remained unchanged in the DG of hypothyroid rats. Basal calcineurin levels and activity, although enhanced in CA1, were reduced in the DG of hypothyroid rats. These findings suggest that the DG may possess a compensatory mechanism whereby calcineurin levels are reduced, to allow sufficient CaMKII activity to produce an apparently normal LTP in hypothyroid rats.

Reduced basal CaMKII levels in hippocampal CA1 region: possible cause of stress-induced impairment of LTP in chronically stressed rats.

Chronic psychosocial stress markedly reduces the expression of high-frequency stimulation (HFS)-evoked early long-term potentiation (LTP) in the CA1 region of the hippocampus of anesthetized rats. Immunoblotting was performed to determine changes in molecular levels of key signaling proteins that might be responsible for this inhibitory effect. Western blot analysis of the CA1 region demonstrates that chronic psychosocial stress decreases basal levels of calcium calmodulin kinase II (CaMKII), phosphorylated (P)-CaMKII, calmodulin, and protein kinase C (PKCgamma) while markedly increasing protein phosphatase 2B (calcineurin) levels. The decrease of basal levels of P-CaMKII may be triggered primarily by excessive dephosphorylation resulting from enhanced basal levels of calcineurin. The decline in the basal levels of the upstream molecules, PKCgamma and calmodulin may be a consequence of the diminished basal P-CaMKII levels. Analysis of signaling molecules in CA1 region of chronically stressed rat subjected to HFS in vivo showed only one difference compared to similarly stimulated control rats; no increase in P-CaMKII levels. Our results suggest that decreased P-CaMKII levels may be primarily responsible for the stress-induced reduction in LTP expression.

Impaired long-term potentiation in obese zucker rats: possible involvement of presynaptic mechanism.

Electrophysiological investigation of basal synaptic transmission and synaptic plasticity in the CA1 region of the hippocampus was carried out in anesthetized obese Zucker rats (OZR). Comparison of the input/output curves of basal field excitatory postsynaptic potential indicates that these are similar in both the OZR and its lean counterpart suggesting that basal synaptic transmission is intact in the OZR. However, high frequency stimulation evokes long-term potentiation (LTP) in the lean rat but not in the OZR. Since post-tetanic potentiation and paired pulse facilitation, forms of short-term potentiation of presynaptic origin, are also severely impaired in the OZR, the results imply that impairment of CA1 hippocampal LTP in these obese rats may be due, in part, to impaired presynaptic function. The results emphasize the potential deleterious effect of obesity on learning and memory functions of the CNS.

Chronic psychosocial stress decreases calcineurin in the dentate gyrus: a possible mechanism for preservation of early ltp.

Chronic psychosocial stress impairs early long-term potentiation (LTP) in the hippocampal CA1 region but not in the dentate gyrus of anesthetized rats. Analysis of putative signaling molecules involved in the expression of LTP was performed to determine the possible reason(s) for the apparent resistance of the LTP of the dentate gyrus to chronic psychosocial stress. Immunoblotting was used to determine possible changes in the basal levels of various fractions of calcium-dependent calmodulin kinase II (CaMKII), phosphorylated CaMKII (P-CaMKII), calmodulin, protein kinase C gamma (PKCgamma) and calcineurin in the dentate gyrus of chronically stressed rats. Western blot analysis revealed that chronic stress significantly decreased the levels of the total CaMKII without affecting P-CaMKII levels. No significant change was detected in the levels of the upstream effectors, calmodulin and PKCgamma. However, chronic stress produced a significant decrease in calcineurin levels. The data suggest that the dentate gyrus of chronically stressed rats may have developed a compensatory mechanism whereby calcineurin levels are reduced to maintain normal P-CaMKII levels, which may be responsible for the normal early LTP of the dentate gyrus of chronically stressed rats. The results of this work will increase understanding of why certain brain regions are more resistant to deleterious effects of conditions that deteriorate learning and memory.

Reduction of elevated arterial blood pressure in obese Zucker rats by inhibition of ganglionic long-term potentiation.

Sustained enhancement of the basal tone of ganglionic transmission is expected to result in an enduring increase in peripheral resistance that would lead to elevated blood pressure. Long-term potentiation of sympathetic ganglia is an activity-dependent long-lasting increase in strength of ganglionic transmission. Therefore, ganglionic long-term potentiation might be involved in the manifestation of neurogenic forms of hypertension. Expression of sympathetic ganglionic long-term potentiation is dependent on activation of 5-HT(3) receptor. We examined the possibility that elevated blood pressure in obese Zucker rat, which is reported to be stress-prone, might be partly due to a neurogenic factor resulting from expression of ganglionic long-term potentiation. Chronic treatment with the 5-HT(3) receptor antagonist ondansetron (0.5 mg/kg/day) caused a significant decrease in blood pressure of the obese Zucker rats without affecting that of normotensive lean Zucker rats. Electropysiological procedures to test for long-term potentiation in isolated ganglia suggest that ganglionic long-term potentiation has been previously expressed in vivo in ganglia from obese Zucker rat but not in those from the normotensive lean Zucker rats. The results indicate that expression of ganglionic long-term potentiation in sympathetic ganglia may be responsible for neurogenic increase in blood pressure, which contributes to the moderate hypertension often seen in the obese Zucker rats.

Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats.

Clinical experience suggests that both hypothyroidism and stress interfere with mental concentration and memory. This electrophysiological study examined the effect of hypothyroidism and stress, separately or combined, on long-term potentiation (LTP), a widely accepted cellular model for learning and memory. Measurements of early LTP (E-LTP) were carried out in the hippocampus of urethane-anesthetized adult Wistar rats. Hypothyroidism was achieved by thyroidectomy, and the 'intruder' stress was used as a model of chronic psychosocial stress. Stimulating electrodes were placed in the left CA3 region and right angular bundle and a recording electrode was placed in the right CA1 or the dentate gyrus (DG). The results showed that in the CA1 region of the hippocampus, hypothyroid or stress partially blocked E-LTP. However, when hypothyroidism and stress were combined, they eliminated E-LTP. In contrast, no significant change in E-LTP was seen in the DG of the three groups of rats. These results suggest that impaired memory because of hypothyroidism or stress may be related to impairment of the E-LTP in the Schaffer collateral synapses but not of that of the perforant path synapses.