Muscarinic Tone Sustains Impulse Flow in the Septohippocampal GABA But Not Cholinergic Pathway: Implications for Learning and Memory

Systemic infusions of the muscarinic cholinergic receptor antagonists atropine and scopolamine (atr/scop) produce an amnesic syndrome in humans, subhuman primates, and rodents. In humans, this syndrome may resemble early symptoms of Alzheimer's disease. Behavioral studies in rats have demonstrated that the medial septum/diagonal band of Broca (MSDB), which sends cholinergic and GABAergic projections to the hippocampus, is a critical locus in mediating the amnesic effects of atr/scop. The amnesic effects of atr/scop in the MSDB have been presumed but not proven to be caused by a decrease in hippocampal acetylcholine (ACh) release after blockade of a muscarinic tone in the MSDB. Using electrophysiological recordings and fluorescent-labeling techniques to identify living septohippocampal neurons in rat brain slices, we now report that, contrary to current belief, a blockade of the muscarinic tone in the MSDB does not decrease impulse flow in the septohippocampal cholinergic pathway; instead, it decreases impulse flow in the septohippocampal GABAergic pathway via M3 muscarinic receptors. We also report that the muscarinic tone in the MSDB is maintained by ACh that is released locally, presumably via axon collaterals of septohippocampal cholinergic neurons. As such, cognitive deficits that occur in various neurodegenerative disorders that are associated with a loss or atrophy of septohippocampal cholinergic neurons cannot be attributed solely to a decrease in hippocampal acetylcholine release. An additional, possibly more important mechanism may be the concomitant decrease in septohippocampal GABA release and a subsequent disruption in disinhibitory mechanisms in the hippocampus. Restoration of impulse flow in the septohippocampal GABA pathway, possibly via M3receptor agonists, may, therefore, be critical for successful treatment of cognitive deficits associated with neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

[1]  C. Pavlides,et al.  Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm. , 1988, Brain research.

[2]  T. Freund,et al.  Convergence and segregation of septal and median raphe inputs onto different subsets of hippocampal inhibitory interneurons , 1992, Brain Research.

[3]  M. Sarter,et al.  Modulation of cognitive processes by transsynaptic activation of the basal forebrain , 1997, Behavioural Brain Research.

[4]  Z. Henderson,et al.  Parvalbumin-immunoreactive, fast-spiking neurons in the medial septum/diagonal band complex of the rat: intracellular recordings in vitro , 1999, Neuroscience.

[5]  I. Izquierdo,et al.  Mechanism of action of scopolamine as an amnestic. , 1989, Trends in pharmacological sciences.

[6]  Allan Levey,et al.  Expression of m1‐m4 muscarinic acetylcholine receptor immunoreactivity in septohippocampal neurons and other identified hippocampal afferents , 1996, The Journal of comparative neurology.

[7]  N. Gorelova,et al.  Role of the afterhyperpolarization in control of discharge properties of septal cholinergic neurons in vitro. , 1996, Journal of neurophysiology.

[8]  B. Westerink,et al.  Characterisation of muscarinic autoreceptors in the septo-hippocampal system of the rat: a microdialysis study. , 1995, European journal of pharmacology.

[9]  W. Härtig,et al.  Selective in vivo fluorescence labelling of cholinergic neurons containing p75NTR in the rat basal forebrain , 1998, Brain Research.

[10]  C. Pavlides,et al.  Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of θ-rhythm , 1988, Brain Research.

[11]  M. Alreja,et al.  Noradrenaline induces IPSCs in rat medial septal/diagonal band neurons: involvement of septohippocampal GABAergic neurons. , 1996, The Journal of physiology.

[12]  C. Léránth,et al.  Cholinergic Excitation of Septohippocampal GABA But Not Cholinergic Neurons: Implications for Learning and Memory , 2000, The Journal of Neuroscience.

[13]  C. Scali,et al.  Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats , 1997, Neuroscience.

[14]  K. Rocklin,et al.  Amnesia induced by Scopolamine and its Temporal Variations , 1967, Nature.

[15]  A. Burkhalter,et al.  Fluorescent latex microspheres as a retrograde neuronal marker for in vivo and in vitro studies of visual cortex , 1984, Nature.

[16]  I. Gartside,et al.  Relationship Between Venous Pressure and tissue Volume During Venous Congestion Plethysmography in Man , 1997, The Journal of physiology.

[17]  M. Kopelman,et al.  Cholinergic 'blockade' as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome. , 1988, Brain : a journal of neurology.

[18]  R. Bartus.  Evidence for a direct cholinergic involvement in the scopolamine-induced amnesia in monkeys: Effects of concurrent administration of physostigmine and methylphenidate with scopolamine , 1978, Pharmacology Biochemistry and Behavior.

[19]  J. Kacza,et al.  Electron microscopic evidence for a cholinergic innervation of GABAergic parvalbumin‐immunoreactive neurons in the rat medial septum , 1998, Journal of neuroscience research.

[20]  P. Dutar,et al.  Acetylcholine excites identified septo-hippocampal neurons in the rat , 1983, Neuroscience Letters.

[21]  D. Olton,et al.  Local modulation of basal forebrain: effects on working and reference memory , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  Robert T. Matthews,et al.  Electrophysiology of AChE-positive neurons in basal forebrain slices , 1986, Neuroscience Letters.

[23]  Larry L. Butcher,et al.  Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain , 1986, Brain Research Bulletin.

[24]  J. Palacios,et al.  Multiplicity of muscarinic autoreceptor subtypes? Comparison of the distribution of cholinergic cells and cells containing mRNA for five subtypes of muscarinic receptors in the rat brain. , 1994, Brain research. Molecular brain research.

[25]  J. Palacios,et al.  Localization of m5 muscarinic receptor mRNA in rat brain examined by in situ hybridization histochemistry , 1990, Neuroscience Letters.

[26]  D. Carpenter,et al.  Action of vasopressin on CA1 pyramidal neurons in rat hippocampal slices , 1984, Brain Research.

[27]  T. Freund,et al.  Disinhibition of rat hippocampal pyramidal cells by GABAergic afferents from the septum. , 1997, The Journal of physiology.

[28]  B. Heimrich,et al.  Postnatal development of muscarinic autoreceptors in the rat brain: lateral and medial septal nuclei and the diagonal band of Broca. , 1999, Brain research. Developmental brain research.

[29]  T. Arendt,et al.  Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. II. Ageing, Korsakoff's disease, Parkinson's disease, and Alzheimer's disease , 1995, The Journal of comparative neurology.

[30]  M. Alreja,et al.  Excitatory effects of muscarine on septohippocampal neurons: involvement of M3 receptors , 1998, Brain Research.

[31]  D. Olton,et al.  Cholinergic manipulations in the medial septal area: age-related effects on working memory and hippocampal electrophysiology , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  P. Dutar,et al.  Septo-hippocampal and other medial septum-diagonal band neurons: electrophysiological and pharmacological properties , 1984, Brain Research.

[33]  M. Frotscher,et al.  Choline acetyltransferase‐immunoreactive neurons and terminals in the rat septal complex: A combined light and electron microscopic study , 1987, The Journal of comparative neurology.

[34]  M. Brann,et al.  Localization of a family of muscarinic receptor mRNAs in rat brain , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  E. Mufson,et al.  Loss of nerve growth factor receptor-containing neurons in Alzheimer's disease: A quantitative analysis across subregions of the basal forebrain , 1989, Experimental Neurology.

[36]  M. Segal.  Properties of rat medial septal neurones recorded in vitro. , 1986, The Journal of physiology.

[37]  Henry Markram,et al.  Electrophysiological characteristics of cholinergic and non-cholinergic neurons in the rat medial septum-diagonal band complex , 1990, Brain Research.

[38]  T. Freund,et al.  GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus , 1988, Nature.

[39]  M. Stewart,et al.  Do septal neurons pace the hippocampal theta rhythm? , 1990, Trends in Neurosciences.

[40]  A. Levey,et al.  Localization of muscarinic M3 receptor protein and M3 receptor binding in rat brain , 1994, Neuroscience.

[41]  M. Frotscher,et al.  Organization of the septal region in the rat brain: Cholinergic‐GABAergic interconnections and the termination of hippocampo‐septal fibers , 1989, The Journal of comparative neurology.

[42]  C. Léránth,et al.  Opioids Suppress IPSCs in Neurons of the Rat Medial Septum/Diagonal Band of Broca: Involvement of μ-Opioid Receptors and Septohippocampal GABAergic Neurons , 2000, The Journal of Neuroscience.

[43]  P. Boer,et al.  A novel approach for studying septo-hippocampal cholinergic neurons in freely moving rats: a microdialysis study with dual-probe design , 1994, Brain Research.

[44]  J. Coyle,et al.  Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. , 1982, Science.