Neuropeptide Y and Memory Processing JOHN E. MORLEY AND JAMES F. FLOOD
Geriatric Research Education and Clinical Center St. Louis Veterans Administration Medical Center St. Louis, Missouri 63125 and Division of Geriatric Medicine St. Louis University Medical School 1402 S . Grand Boulevard St. Louis, Missouri 63104 Numerous neurotransmitters have been demonstrated to modulate memory (TABLE1). Neuropeptide Y (NPY) has been demonstrated to modulate a variety of behaviors. NPY is highly concentrated in the hippocampus and amygdala.2 The highest concentrations of NPY binding sites are in the hippocampu~.~ As both the amygdala and hippocampus are known to be important areas involved in memory processing, we postulated that NPY may play a role in memory modulation.
'
Memory Processing and Central Injections of NPY Posttraining intracerebroventricular (ICV) administration of NPY to mice, which were undertrained, on a step-down passive avoidance task, resulted in improved retention when the mice were re-tested 7 days later.4 A maximum improvement in memory was seen between 0.25 and 0.5 micrograms of NPY and the dose reponse demonstrated a typical inverted-U shaped curve. Next, the effects of NPY on memory retention administered ICV immediately after training in a T-maze active avoidance task were tested. NPY improved retention in this active avoidance task with maximum improvement occurring at a dose of 5 micrograms. NPY free acid was ineffective at improving memory in this paradigm, suggesting a specific effect of the active form of NPY. Peripheral administration of NPY had no effect on memory processing, showing that NPY was exerting its effect within the central nervous system and not by diffusing out of the brain into the periphery. The effect of NPY on memory retention was time dependent with the effect dissipating when NPY was administered 90 minutes after training indicating that the effect of NPY on retention testing was not due to a proactive effect of the peptide. NPY had no effect on acquisition of T-maze footshock avoidance confirming a specific effect of NPY on memory retention. Previous studies have demonstrated that approximately one-tenth of the optimal dose of a memory retention enhancing agent will improve recall when administered just before retention One week after T-maze footshock avoidance training NPY was administered ICV immediately prior to retention testing. NPY enhanced retention with the optimal dose being 0.25 micrograms of NPY.4 As NPY did not alter acquisition, this enhanced recall most probably reflects enhanced retrieval of previously stored memories. Amnesia produced by inhibitors of rotein synthesis can be reversed by numerous neurotransmitter agonists and hormones.' Similarly, NPY was shown to reverse amnesia .~ is an produced by the protein synthesis inhibitor, anisomycin (20 ~ n g / k g ) Scopolamine acetylocholine receptor antagonist. Scopolamine induces amnesia. Scopolamine-induced 226
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amnesia is reversed by a variety of neurotransmitters.’ Mice receiving saline had an 80% recall score; scopolamine treated mice had only a 13% recall score demonstrating the amnestic effect of scopolamine. Mice receiving both scopolamine and NPY had an 80% recall score, demonstrating the ability of NPY to reverse the scopolamine-induced amne~ia.~ Recently food ingestion has been demonstrated to enhance memory retention for a T-maze aversive test.’ NPY is a potent anorexigenic agent.’ This suggested that the memory enhancement produced by NPY could be secondary to its ability to increase food intake. To test this possibility, we tested the ability of NPY to enhance memory when food was not available for 3 hours after training. NPY was equally effective at enhancing memory retention when food was not a ~ a i l a b l eTherefore, .~ the NPY effect on memory retention is a primary one and not secondary to its ability to enhance food intake. Administration of optimal memory retention enhancing doses of cholinergic agonists such as arecoline and tacrine impair retention when mice are well (over) trained rather than under (poorly) trained. Other neurotransmitters that enhance memory retention will impair memory retention in well trained mice. NPY is no exception to this rule. When mice were given 5 trials instead of 4, footshock was increased from 0.30 to 0.35 mA and the buzzer was louder (65dB compared to 55dB), 73% of controls remembered the task TABLE 1. Neurotransmitters Known to Modulate Memory
Memory Enhancers Acetylcholine Alpha-noradrenergic Serotonin Dopamine Somatostatin Cholecystokinin Vasopressin
Amnestic Agents Gama-amino butyne acid Beta-endorphin Vasoactive intestinal peptide
ACTH
Neuropeptide Y NeurooeDtide K compared to 20% or less in the undertrained condition. NPY administered ICV at a dose of 5 micrograms impaired retention, with a recall score of only 13%.4 Thus NPY follows the general rule for memory retention enhancing drugs, L e . , that these agents are amnestic in overtrained animals. To summarize, NPY when administered ICV, is a potent memory enhancing agent. NPY demonstrates many parallels to the memory enhancement seen with the cholinergic agent, arecholine (TABLE2). Site of Action
To examine the forebrain sites at which NPY produced its effect on memory retention we injected 0 to 1 microgram NPY or saline in a volume of 0.5 microliters into the caudal and rostral portion of hippocampus, the septum, the amygdala, the caudate and the thalamus.” NPY, at an optimum dose of 0.5 pg, enhanced memory for the T-maze footshock active avoidance task when injected into the rostral hippocampus and the septum. NPY was amnestic when injected into the amygdala and caudal hippocampus. Injections of NPY into the caudate and thalamus were without effect. Injection of NPY into cortical sites just above the rostral hippocampus and septum also failed to produce an
ANNALS NEW YORK ACADEMY OF SCIENCES
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Comparison between the Effects of Neuropeptide Y and Arecoline (NPY) on Memory
TABLE 2.
Acquisition Memory retention Reverses anisomycin amnesia Reverses scopolamine amnesia Memory recall Enhanced memory in old mice Amnesia in overtrained mice
NPY
Arecoline
no effect enhanced Yes Yes enhanced Yes yes
no effect enhanced Yes Yes enhanced Yes yes
effect on memory retention. This confirmed the specificity of the sites of action at which NPY modulates memory retention. The physiologic role of NPY on memory retention was tested by passively administering NPY antibodies into these structures that had been shown to be NPY sensitive. NPY antibodies were amnestic when injected into the rostral hippocampus and septum and enhanced memory retention when injected into the caudal hippocampus and the amygdala. l o These effects of NPY antibody administration were opposite to those obtained with NPY administration. To further examine the specificity of the effect of NPY, we examined the effect of localized injections of a similar size neuropeptide, Neuropeptide K. NPK is a 36-amino acid peptide which contains the sequence of the substance P presursor, neurokinin A, as amino acids 27 to 36 of its C-terminus. Neuropeptide K is present in high concentrations in the hippocampus," and neurokinin A receptors are present in the hippocampus and the amygdala." Both NPK and neurokinin A have been shown to enhance memory for the aversive T-maze paradigm when administered intracerebroverntricularly immediately af3 compares the effects of localized injections of neuropeptide K to ter training." TABLE those of NPY. Like NPY, neuropeptide K enhanced memory when injected into the rostral hippocampus. However, neuropeptide K also enhanced memory in two areas where NPY was amnestic, viz, the caudal hippocampus and amygdala. Neuropeptide K produced no effects in the septum, an area in which NPY enhanced memory retention. These studies show that NPY and NPK have specific sites within the central nervous system at which they modulate memory and that the memory modulating effects of 36-amino-acid peptides are not due to nonspecific effects of peptides of this size. Overall this series of studies has demonstrated that NPY is a physiological modulator of memory. In addition, the effects of NPY on memory are dependent on the anatomic site at which it is released. This anatomic specificity supports the concept that NPY is acting
3. Comparison of the Effects of Localized Injections of Neuropeptide Y (NPY) and Neuropeptide K (NPK) on Memory Retention TABLE
Effect on Memory Anatomic Site
H yppocampus-rostral-caudal Amygdala Septum Thalamus
NPY
NPK
enhanced amnestic amnestic enhanced no effect
enhanced enhanced enhanced no effect no effect
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as a neuromodulator, perhaps through modulating the release or receptor function of a co-released classical neurotransmitter.
NPY
Receptors Memory and Feeding
NPY is the most potent orexigenic agent yet to be discovered. l4 It produces its effects on feeding predominantly in the ventromedial hypothalamus and in the paraventricular nucleus of the hypothalamus,’ as well as in structures associated with the fourth ventricle. l4 Recently it has been demonstrated that there are two classes of NPY receptors; a postsynaptic (Yl) receptor and a presynaptic (Y,)receptor. Shorter NPY fragments bind only to the Y, receptor. Y, receptors are present in neuronal membranes of the hippocampus.” Our studies showed that the shorter NPY segments were capable of producing memory enhancement.I6 On the other hand, only the intact fragment was capable of producing food ingestion. Thus the memory effects of NPY appear to involve
Basket Cells
Pyramidal Cell
Pyramidal Cells
FIGURE 1. (A) Neuropeptide Y (NPY) could be co-released with gamma amino butyric acid (GABA) and NPY could feedback presynaptically on the basket cell to inhibit further release of GABA. Thus GABA would no longer inhibit the tiring of the pyramidal cell containing glutamate. Glutamate enhances memory retention. (B)A similar scenario is postulated for NPY inhibiting the release of vasoactive intestinal peptide (VIP). Alternatively VIP could act on a separate set of pyramidal cells.
the presynaptic (Y,) receptors, while the feeding effects utilize postsynaptic (Y I ) receptors. Mechanism by Which NPY Enhances Memory
The activity of classical neurotransmitter activity resulting from an action potential can be modified by coexisting classical neurotransmitters. NPY is found in basket-type cells in the hippocampus that synapse on perikarya and dendrites of pyramidal cells in the hippocampus. In general, the major neurotransmitter in basket cells is gamma amino butyric acid (GABA).’* Application of NPY to the hippocampus reduces spike amplitude when this is recorded either extracellularly or from pyramidal cell^;^^.^^ thus suggesting its effects are mediated by an interneuron. NPY fails to alter the excitatory effect of glutamate applied iontophoretically to the hippocampus. l9 As NPY acts predominantly on the presynaptic (Y2)receptor to enhance memory, we suggest that NPY produces its memory enhancing effect by inhibiting release of GABA from basket cells, and thus facilitating firing of glutamate containing pyramidal cells (FIG. 1A).
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ANNALS NEW YORK ACADEMY OF SCIENCES
Vasoactive intestinal peptide (VIP) is a potent amnestic agent when injected directly into the rostral portion of the hippocampus (unpublished observations). This effect of VIP is not reversed by co-administration of NPY, but is reversed by the cholinergic analog, 1B gives a scheme by which NPY would be co-released with GABA, arecholine. FIGURE and VIP would be released from a separate basket cell. Alternatively, all three neurotransmitters could be co-released. These studies allow the beginnings of an understanding of how classical neurotransmitters and neuropeptides might interact to modulate memory.
Alzheimer’s Disease and Neuropeptide Y Hippocampal neurons and axons containing immunoreactive NPY are involved in plaque formation in Alzheimer’s Disease.2’.22NPY is present in the same cell bodies as somatostatin and these cell bodies ar involved in the pathological processes of Alzheimer’s disease. 23 Measurements of immunoreactive NPY have suggested a reduced level in cerebral cortical cells of patients with Alzheimer’s disease,24 but other studies have failed to show changes in cortical ~ e l l s . Increased ~ ~ * ~ levels ~ of immunoreactive NPY have been found in the substantia innominata of patients with Alzheimer’s disease.*’ Overall it appears that chahges in immunoreactive NPY occur in Alzheimer’s disease or only in some forms of Alzheimer’s disease. Cerebrospinal fluid levels of immunoreactive NPY were reduced by 18% in patients with dementia associated with extrapyramidal signs but not in those with dementia not associated with extrapyramidal signs.** These studies suggest a possible role for NPY in the pathogenesis of Alzheimer’s disease.
CONCLUSION Memory retention appears to be under the regulation of numerous neurotransmitters. Many of these seem to play a modulatory role in allowing the development of the memory trace. NPY appears to be a potent physiological modulator of memory. The effects of NPY are anatomically specific. Within the rostral hippocampus NPY may exert its effects by being co-released with GABA from basket cells in the hippocampus. NPY would then feedback on presynaptic receptors (YJ to inhibit the release of GABA. Lack of release of GABA would allow the unimpeded release of the memory enhancing neurotransmitter, glutamate. Conflicting results exist concerning the effect of Alzheimer’s disease on NPY levels measured by radioimmunoassay. It is possible that an imbalance of NPY together with other neurotransmitters may play a role in the pathogenesis of Alzheimer’s disease. REFERENCES 1 . GRAY,T.S. & J. E. MORLEY. 1986. Life Sci. 38: 389-401. 2. ALLEN,Y . S., T. E., ADRIAN, J . M. ALLEN,K. TATEMOTO, T. J . CROW,S . R. BLOOM& J . M. POLLAK. 1983. Science 221: 877-879. 3. CHANG, R . S. L., V. J . LOTTI,T-B. CHEN,D. J. CERIRO & P. J. KLING. 1985. Life Sci. 37: 2111-2112. J . F., E. N. HERNANDEZ& J . E. MORLEY. 1987. Brain Res. 421: 280-290. 4. FLOOD, 5 . FLOOD,J . F., G . E. SMITH & A. CHERKIN. 1986. J . Pharmacol. 16: 39-49. 6. FLOOD,J. F. & A. C. CHERKIN. 1987. Psychopharmacology 93: 36-43. 7. FLOOD,J . F., A. C. CHERKIN & J . E. MORLEY. 1987. Brain Res. 422: 218-234. 8. FLOOD,J . F., G . E. SMITH& J . E. MORLEY. 1987. Science 236: 832-834.
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J. E., A. S. LEVINE, B. A. GOSNELL, J. KNEIP& M. GRACE.1987, Am. J. Physiol. 9. MORLEY, 252: R599-R609. 10. FLOOD,J. F., M. L. BAKER, E. N. HERNANDEZ& J. E. MORLEY.1989. Brain Res. 503: 73-82. 1 1 . ARAI. H.& P. C. EMSON.1986. Brain Res. 3% 240-249. 12. SAFFROY, Y.TORRENS, J . BESSEYRE, L. BERGSTROM & J. GLOWINSKI. M., J . C. BEAUJOUAN, 1988. Peptides 9: 227-241. E. N . HERNANDEZ & 1 . E. MORLEY. 1990. Brain Res. In press. 13. FLOOD,J. F., M. L. BAKER, 14. MORLEY, J. E. 1987. Endocr. Rev. 8: 256-287. 15. SCHWARTZ, T. W.,J. FUHLENDORFF, N. LANGELAND, H. TH~GERSEN, J. C. JORCENSEN & S. P. SHECK.1989. In Nobel Symposium XIV: Neuropeptide Y. V. Mutt, T.Hokfelt & K. Fuxe, Eds. Raven Press. New York. 16. FLOOD,J. F. & J. E. MORLEY. 1989. Peptides 10 963-966. S. DAVlEs & V. CHAN-PALAY. 1985. J. Comp. Neurol. 239: 17. KOHLER, C., L. ERIKSSON, 420-430. 18. SERON,L & C. E. RIBAK.1984. J. Neurocytol. 13: 215-225. 19. COLMERS, W.F., K. LUBOWIAK & Q. J. PITMAN.1987. 1. Physiol. 383: 285-299. R. W.GREENE & V. CHAN-PALAY. 1987. J. Comp. Neurol. 20. HAAS,M. L., A. HERMANN, 257: 208-215. V., W.LANG& U. HAESLER. 1986. J. Comp. Neurol. 248: 376-384. 21. CHAN-PALAY, D. & P. C. EMSON.1985. Biochem. Biophys. Res. Commun. 126: 289-294. 22. DAWBAM, 23. NAKAMURA, S. & S. R. VINCENT.1986. Brain Res. 370: 11-20. 24. BEAL,M. F., M. F. MAZUREK, G . K. CHALTA& J. B. MASTER.1984. J. Neurol. Sci. 64:325-331. 1984. Neurosci. Lett. 52: 213-217. D., M. N. ROSSOR& C. Q. MOUNTJOY. 25. DAWBAM, 1986. Neurosci. Lett. 63: 71-75. 26. FOSTER,N. L., C. A. TAMMINGA & T.L. O’DONOHUE. 27. ALLEN,J. M., I. N. FERRlER & G . W.ROBERTS. 1984. J. Neurol. Sci. 64: 325-331. 28. ATACK,J. R., M. F. BEAL,C. MAY,J. A. KAYE,M. F. MAZUREK, A. D. KAY& S. 1. RAPWRT. 1988. Arch. Neurol. 45: 269-274.
Geriatric Research Education and Clinical Center St. Louis Veterans Administration Medical Center St. Louis, Missouri 63125 and Division of Geriatric Medicine St. Louis University Medical School 1402 S . Grand Boulevard St. Louis, Missouri 63104 Numerous neurotransmitters have been demonstrated to modulate memory (TABLE1). Neuropeptide Y (NPY) has been demonstrated to modulate a variety of behaviors. NPY is highly concentrated in the hippocampus and amygdala.2 The highest concentrations of NPY binding sites are in the hippocampu~.~ As both the amygdala and hippocampus are known to be important areas involved in memory processing, we postulated that NPY may play a role in memory modulation.
'
Memory Processing and Central Injections of NPY Posttraining intracerebroventricular (ICV) administration of NPY to mice, which were undertrained, on a step-down passive avoidance task, resulted in improved retention when the mice were re-tested 7 days later.4 A maximum improvement in memory was seen between 0.25 and 0.5 micrograms of NPY and the dose reponse demonstrated a typical inverted-U shaped curve. Next, the effects of NPY on memory retention administered ICV immediately after training in a T-maze active avoidance task were tested. NPY improved retention in this active avoidance task with maximum improvement occurring at a dose of 5 micrograms. NPY free acid was ineffective at improving memory in this paradigm, suggesting a specific effect of the active form of NPY. Peripheral administration of NPY had no effect on memory processing, showing that NPY was exerting its effect within the central nervous system and not by diffusing out of the brain into the periphery. The effect of NPY on memory retention was time dependent with the effect dissipating when NPY was administered 90 minutes after training indicating that the effect of NPY on retention testing was not due to a proactive effect of the peptide. NPY had no effect on acquisition of T-maze footshock avoidance confirming a specific effect of NPY on memory retention. Previous studies have demonstrated that approximately one-tenth of the optimal dose of a memory retention enhancing agent will improve recall when administered just before retention One week after T-maze footshock avoidance training NPY was administered ICV immediately prior to retention testing. NPY enhanced retention with the optimal dose being 0.25 micrograms of NPY.4 As NPY did not alter acquisition, this enhanced recall most probably reflects enhanced retrieval of previously stored memories. Amnesia produced by inhibitors of rotein synthesis can be reversed by numerous neurotransmitter agonists and hormones.' Similarly, NPY was shown to reverse amnesia .~ is an produced by the protein synthesis inhibitor, anisomycin (20 ~ n g / k g ) Scopolamine acetylocholine receptor antagonist. Scopolamine induces amnesia. Scopolamine-induced 226
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amnesia is reversed by a variety of neurotransmitters.’ Mice receiving saline had an 80% recall score; scopolamine treated mice had only a 13% recall score demonstrating the amnestic effect of scopolamine. Mice receiving both scopolamine and NPY had an 80% recall score, demonstrating the ability of NPY to reverse the scopolamine-induced amne~ia.~ Recently food ingestion has been demonstrated to enhance memory retention for a T-maze aversive test.’ NPY is a potent anorexigenic agent.’ This suggested that the memory enhancement produced by NPY could be secondary to its ability to increase food intake. To test this possibility, we tested the ability of NPY to enhance memory when food was not available for 3 hours after training. NPY was equally effective at enhancing memory retention when food was not a ~ a i l a b l eTherefore, .~ the NPY effect on memory retention is a primary one and not secondary to its ability to enhance food intake. Administration of optimal memory retention enhancing doses of cholinergic agonists such as arecoline and tacrine impair retention when mice are well (over) trained rather than under (poorly) trained. Other neurotransmitters that enhance memory retention will impair memory retention in well trained mice. NPY is no exception to this rule. When mice were given 5 trials instead of 4, footshock was increased from 0.30 to 0.35 mA and the buzzer was louder (65dB compared to 55dB), 73% of controls remembered the task TABLE 1. Neurotransmitters Known to Modulate Memory
Memory Enhancers Acetylcholine Alpha-noradrenergic Serotonin Dopamine Somatostatin Cholecystokinin Vasopressin
Amnestic Agents Gama-amino butyne acid Beta-endorphin Vasoactive intestinal peptide
ACTH
Neuropeptide Y NeurooeDtide K compared to 20% or less in the undertrained condition. NPY administered ICV at a dose of 5 micrograms impaired retention, with a recall score of only 13%.4 Thus NPY follows the general rule for memory retention enhancing drugs, L e . , that these agents are amnestic in overtrained animals. To summarize, NPY when administered ICV, is a potent memory enhancing agent. NPY demonstrates many parallels to the memory enhancement seen with the cholinergic agent, arecholine (TABLE2). Site of Action
To examine the forebrain sites at which NPY produced its effect on memory retention we injected 0 to 1 microgram NPY or saline in a volume of 0.5 microliters into the caudal and rostral portion of hippocampus, the septum, the amygdala, the caudate and the thalamus.” NPY, at an optimum dose of 0.5 pg, enhanced memory for the T-maze footshock active avoidance task when injected into the rostral hippocampus and the septum. NPY was amnestic when injected into the amygdala and caudal hippocampus. Injections of NPY into the caudate and thalamus were without effect. Injection of NPY into cortical sites just above the rostral hippocampus and septum also failed to produce an
ANNALS NEW YORK ACADEMY OF SCIENCES
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Comparison between the Effects of Neuropeptide Y and Arecoline (NPY) on Memory
TABLE 2.
Acquisition Memory retention Reverses anisomycin amnesia Reverses scopolamine amnesia Memory recall Enhanced memory in old mice Amnesia in overtrained mice
NPY
Arecoline
no effect enhanced Yes Yes enhanced Yes yes
no effect enhanced Yes Yes enhanced Yes yes
effect on memory retention. This confirmed the specificity of the sites of action at which NPY modulates memory retention. The physiologic role of NPY on memory retention was tested by passively administering NPY antibodies into these structures that had been shown to be NPY sensitive. NPY antibodies were amnestic when injected into the rostral hippocampus and septum and enhanced memory retention when injected into the caudal hippocampus and the amygdala. l o These effects of NPY antibody administration were opposite to those obtained with NPY administration. To further examine the specificity of the effect of NPY, we examined the effect of localized injections of a similar size neuropeptide, Neuropeptide K. NPK is a 36-amino acid peptide which contains the sequence of the substance P presursor, neurokinin A, as amino acids 27 to 36 of its C-terminus. Neuropeptide K is present in high concentrations in the hippocampus," and neurokinin A receptors are present in the hippocampus and the amygdala." Both NPK and neurokinin A have been shown to enhance memory for the aversive T-maze paradigm when administered intracerebroverntricularly immediately af3 compares the effects of localized injections of neuropeptide K to ter training." TABLE those of NPY. Like NPY, neuropeptide K enhanced memory when injected into the rostral hippocampus. However, neuropeptide K also enhanced memory in two areas where NPY was amnestic, viz, the caudal hippocampus and amygdala. Neuropeptide K produced no effects in the septum, an area in which NPY enhanced memory retention. These studies show that NPY and NPK have specific sites within the central nervous system at which they modulate memory and that the memory modulating effects of 36-amino-acid peptides are not due to nonspecific effects of peptides of this size. Overall this series of studies has demonstrated that NPY is a physiological modulator of memory. In addition, the effects of NPY on memory are dependent on the anatomic site at which it is released. This anatomic specificity supports the concept that NPY is acting
3. Comparison of the Effects of Localized Injections of Neuropeptide Y (NPY) and Neuropeptide K (NPK) on Memory Retention TABLE
Effect on Memory Anatomic Site
H yppocampus-rostral-caudal Amygdala Septum Thalamus
NPY
NPK
enhanced amnestic amnestic enhanced no effect
enhanced enhanced enhanced no effect no effect
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as a neuromodulator, perhaps through modulating the release or receptor function of a co-released classical neurotransmitter.
NPY
Receptors Memory and Feeding
NPY is the most potent orexigenic agent yet to be discovered. l4 It produces its effects on feeding predominantly in the ventromedial hypothalamus and in the paraventricular nucleus of the hypothalamus,’ as well as in structures associated with the fourth ventricle. l4 Recently it has been demonstrated that there are two classes of NPY receptors; a postsynaptic (Yl) receptor and a presynaptic (Y,)receptor. Shorter NPY fragments bind only to the Y, receptor. Y, receptors are present in neuronal membranes of the hippocampus.” Our studies showed that the shorter NPY segments were capable of producing memory enhancement.I6 On the other hand, only the intact fragment was capable of producing food ingestion. Thus the memory effects of NPY appear to involve
Basket Cells
Pyramidal Cell
Pyramidal Cells
FIGURE 1. (A) Neuropeptide Y (NPY) could be co-released with gamma amino butyric acid (GABA) and NPY could feedback presynaptically on the basket cell to inhibit further release of GABA. Thus GABA would no longer inhibit the tiring of the pyramidal cell containing glutamate. Glutamate enhances memory retention. (B)A similar scenario is postulated for NPY inhibiting the release of vasoactive intestinal peptide (VIP). Alternatively VIP could act on a separate set of pyramidal cells.
the presynaptic (Y,) receptors, while the feeding effects utilize postsynaptic (Y I ) receptors. Mechanism by Which NPY Enhances Memory
The activity of classical neurotransmitter activity resulting from an action potential can be modified by coexisting classical neurotransmitters. NPY is found in basket-type cells in the hippocampus that synapse on perikarya and dendrites of pyramidal cells in the hippocampus. In general, the major neurotransmitter in basket cells is gamma amino butyric acid (GABA).’* Application of NPY to the hippocampus reduces spike amplitude when this is recorded either extracellularly or from pyramidal cell^;^^.^^ thus suggesting its effects are mediated by an interneuron. NPY fails to alter the excitatory effect of glutamate applied iontophoretically to the hippocampus. l9 As NPY acts predominantly on the presynaptic (Y2)receptor to enhance memory, we suggest that NPY produces its memory enhancing effect by inhibiting release of GABA from basket cells, and thus facilitating firing of glutamate containing pyramidal cells (FIG. 1A).
230
ANNALS NEW YORK ACADEMY OF SCIENCES
Vasoactive intestinal peptide (VIP) is a potent amnestic agent when injected directly into the rostral portion of the hippocampus (unpublished observations). This effect of VIP is not reversed by co-administration of NPY, but is reversed by the cholinergic analog, 1B gives a scheme by which NPY would be co-released with GABA, arecholine. FIGURE and VIP would be released from a separate basket cell. Alternatively, all three neurotransmitters could be co-released. These studies allow the beginnings of an understanding of how classical neurotransmitters and neuropeptides might interact to modulate memory.
Alzheimer’s Disease and Neuropeptide Y Hippocampal neurons and axons containing immunoreactive NPY are involved in plaque formation in Alzheimer’s Disease.2’.22NPY is present in the same cell bodies as somatostatin and these cell bodies ar involved in the pathological processes of Alzheimer’s disease. 23 Measurements of immunoreactive NPY have suggested a reduced level in cerebral cortical cells of patients with Alzheimer’s disease,24 but other studies have failed to show changes in cortical ~ e l l s . Increased ~ ~ * ~ levels ~ of immunoreactive NPY have been found in the substantia innominata of patients with Alzheimer’s disease.*’ Overall it appears that chahges in immunoreactive NPY occur in Alzheimer’s disease or only in some forms of Alzheimer’s disease. Cerebrospinal fluid levels of immunoreactive NPY were reduced by 18% in patients with dementia associated with extrapyramidal signs but not in those with dementia not associated with extrapyramidal signs.** These studies suggest a possible role for NPY in the pathogenesis of Alzheimer’s disease.
CONCLUSION Memory retention appears to be under the regulation of numerous neurotransmitters. Many of these seem to play a modulatory role in allowing the development of the memory trace. NPY appears to be a potent physiological modulator of memory. The effects of NPY are anatomically specific. Within the rostral hippocampus NPY may exert its effects by being co-released with GABA from basket cells in the hippocampus. NPY would then feedback on presynaptic receptors (YJ to inhibit the release of GABA. Lack of release of GABA would allow the unimpeded release of the memory enhancing neurotransmitter, glutamate. Conflicting results exist concerning the effect of Alzheimer’s disease on NPY levels measured by radioimmunoassay. It is possible that an imbalance of NPY together with other neurotransmitters may play a role in the pathogenesis of Alzheimer’s disease. REFERENCES 1 . GRAY,T.S. & J. E. MORLEY. 1986. Life Sci. 38: 389-401. 2. ALLEN,Y . S., T. E., ADRIAN, J . M. ALLEN,K. TATEMOTO, T. J . CROW,S . R. BLOOM& J . M. POLLAK. 1983. Science 221: 877-879. 3. CHANG, R . S. L., V. J . LOTTI,T-B. CHEN,D. J. CERIRO & P. J. KLING. 1985. Life Sci. 37: 2111-2112. J . F., E. N. HERNANDEZ& J . E. MORLEY. 1987. Brain Res. 421: 280-290. 4. FLOOD, 5 . FLOOD,J . F., G . E. SMITH & A. CHERKIN. 1986. J . Pharmacol. 16: 39-49. 6. FLOOD,J. F. & A. C. CHERKIN. 1987. Psychopharmacology 93: 36-43. 7. FLOOD,J . F., A. C. CHERKIN & J . E. MORLEY. 1987. Brain Res. 422: 218-234. 8. FLOOD,J . F., G . E. SMITH& J . E. MORLEY. 1987. Science 236: 832-834.
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