Elsevier

Progress in Neurobiology

Volume 55, Issue 6, 1 August 1998, Pages 651-658
Progress in Neurobiology

First one in, last one out: the role of GABAergic transmission in generation and degeneration

https://doi.org/10.1016/S0301-0082(98)00024-0Get rights and content

Abstract

This paper is the result of discussions between scientists working in widely separated areas, united by an interest in the hippocampus. The discussions focused on the possible role of GABA in the development and maturation of the hippocampus and in neurodegeneration in Alzheimer's disease (AD). GABA neurons are among the first to differentiate in the hippocampus and the properties of GABA neurotransmission in the developing hippocampus are distinct from those in the adult. GABAergic transmission may play a role in the clustering and maturation of GABA receptors, as well as of receptors for other neurotransmitters. The development and maturation of synaptic connections involves changes in the organization of the cytoskeleton, and mechanical force generation is probably required to establish appropriate points of contact. This generation of force may require coupling of specific receptors to the cytoskeleton through specialized proteins. In AD, much of the developmental process is progressively unraveled in the hippocampus, as afferent fibers, most notably from entorhinal excitatory neurons and from basal forebrain cholinergic cells, degenerate. This denervation undoubtedly has consequences for receptor systems, dendritic morphology and the underlying cytoskeleton. GABA neurons remain in the AD hippocampus, and may actually contribute to abnormal firing and degeneration of remaining pyramidal neurons. This attempt to bring together data from different areas of research has allowed the development of a scheme which identifies significant specific gaps in our knowledge, which could be readily filled by focused experimental work.

Introduction

This paper is an attempt to pull together observations from widely separated areas of research with the aim of generating new ideas and testable hypotheses on the role of GABAergic neurotransmission in neuronal development and degeneration. Central to this paper is the notion that GABA is one of the first functional neurotransmitter systems to develop in the hippocampus, and that GABA synapses may play a major role in pyramidal neuron maturation. As a consequence of the neurodegeneration of Alzheimer's disease (AD), GABAergic neurons may be left as the major functional neurotransmitter systems in the hippocampus of these patients. In the developing hippocampus, there is evidence that GABAergic transmission is depolarizing, facilitating calcium entry into neurons, this being required for maturation of other receptor systems. If GABAergic transmission were to revert to a similar state in the hippocampus of patients with AD, the resulting calcium influx may participate in both abnormal firing of the hippocampal pyramidal cells, as well as in their degeneration (Fig. 1).

Section snippets

Morphological maturation of hippocampal neurons

Developmental studies have shown that interneurons in the hippocampal formation are generated prenatally (Bayer, 1980; Amaral and Kurz, 1985; Lübbers et al., 1985; Soriano et al., 1989) and turn immunopositive for glutamate decarboxylase (GAD) at about postnatal day 1–2 (Nitsch et al., 1990). At that time, pyramidal neurons in the hippocampus exhibit a rather immature dendritic arbor with only a short stem dendrite arising from the apical cell pole (Minkwitz and Holz, 1975; Minkwitz, 1976)

Dendritic regression and axonal sprouting following deafferentation

Partial deafferentation of both dentate and hippocampal neurons results in dramatic changes of their dendritic arborization. Entorhinal cortex lesions and a subsequent loss of perforant path fibers normally innervating the distal portions of these neurons result in an initial retraction of the most distal dendritic segments. Some of these retracted dendritic tips exhibit terminal swellings (Nitsch and Frotscher, 1991; Diekmann et al., 1996). Further retraction results in a rarefied dendritic

Conclusions

These discussions suggest that progressive deafferentation of the hippocampus in AD may be responsible for both cytoskeletal abnormalities and the ultimate death of the pyramidal cells. There may be a variety of direct and indirect effects at work. The deafferentation is likely to cause dendritic retraction by loss of mechanical support, and cytoskeletal changes may directly result from this loss of receptor/cytoskeletal interactions. Changes in receptor activation may also lead to alterations

References (96)

  • C.C. Garner et al.

    Microtubule-associated proteins MAP5 and MAP1x: closely related components of the neuronal cytoskeleton with different cytoplasmic distributions in the developing brain

    Brain Res. Molec. Brain Res.

    (1989)
  • B.I. Giasson et al.

    Aberrant stress-induced phosphorylation of perikaryal neurofilaments

    J. biol. Chem.

    (1996)
  • B.G. Gold et al.

    Regulation of aberrant neurofilament phosphorylation in neuronal perikarya. IV. Evidence for the involvement of two signals

    Brain Res.

    (1993)
  • G.F. Hall et al.

    Axotomy-induced neurofilament phosphorylation is inhibited in situ by microinjection of PKA and PKC inhibitors into identified lamprey neurons

    Neuron

    (1993)
  • E. Hanse et al.

    Activity-dependent wiring of the developing hippocampal neuronal circuit

    Sem. Cell Dev. Biol.

    (1997)
  • T. Herdegen et al.

    The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration

    Trends Neurosci.

    (1997)
  • B.T. Hyman et al.

    A direct demonstration of the perforant pathway terminal zone in Alzheimer's disease using the monoclonal antibody Alz-50

    Brain Res.

    (1988)
  • A. Kenessey et al.

    The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments

    Brain Res.

    (1993)
  • J. Kirsch et al.

    Widespread expression of gephyrin, a putative receptor-tubulin linker protein, in rat brain

    Brain Res.

    (1993)
  • J. Kirsch et al.

    Targeting of glycine receptor subunits to gephyrin-rich domains in transfected human embryonic kidney cells

    Molec. cell. Neurosci.

    (1995)
  • J. Kirsch et al.

    The 93-kDa glycine receptor-associated protein binds to tubulin

    J. biol. Chem.

    (1991)
  • P. Klosen et al.

    Perikaryal neurofilament phosphorylation in axotomized and 6-OH-dopamine-lesioned CNS neurons

    Brain Res.

    (1990)
  • K.S. Kosik et al.

    Developmentally regulated expression of specific tau sequences

    Neuron

    (1989)
  • X. Leinekugel et al.

    Ca2+ oscillations mediated by the synergistic excitatory actions of GABA(A) and NMDA receptors in the neonatal hippocampus

    Neuron

    (1997)
  • G.K. Lloyd et al.

    GABAA receptor complex function in frontal cortex membranes from control and neurological patients

    Eur. J. Pharmac.

    (1991)
  • S. Lovestone et al.

    Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells

    Curr. Biol.

    (1994)
  • K. Lübbers et al.

    Neurogenesis of GABAergic neurons in the dentate gyrus: a combined autoradiographic and immunocytochemical study

    Neurosci. Lett.

    (1985)
  • G. Meyer et al.

    Identification of a gephyrin binding motif on the glycine receptor b subunit

    Neuron

    (1995)
  • T.J. Mitchison et al.

    Actin-based cell motility and cell locomotion

    Cell

    (1996)
  • R. Nitsch et al.

    Maintanance of peripheral dentrites of GABergic neurons requires specific input

    Brain Res.

    (1991)
  • R. Nitsch et al.

    Late appearance of parvalbumin-immunoreactivity in the development of GABAergic neurons in the rat hippocampus

    Neurosci. Lett.

    (1990)
  • E.K. Perry et al.

    Necropsy evidence of central cholinergic deficits in senile dementia

    Lancet

    (1977)
  • E.K. Perry et al.

    Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue

    J. Neurol. Sci.

    (1977)
  • R.H. Perry et al.

    Neuropeptides in Alzheimer's disease, depression and schizophrenia. A post mortem analysis of vasoactive intestinal peptide and cholecystokinin in cerebral cortex

    J. Neurol. Sci.

    (1981)
  • F. Pfeiffer et al.

    Purification by affinity chromatography of the glycine receptor of rat spinal cord

    J. biol. Chem.

    (1982)
  • M.N. Rossor et al.

    Normal cortical concentration of cholecystokinin-like immunoreactivity with reduced choline acetyltransferase activity in senile dementia of Alzheimer type

    Life Sci.

    (1981)
  • C.C. Smith et al.

    Amino acid release from biopsy samples of temporal neocortex from patients with Alzheimer's disease

    Brain Res.

    (1983)
  • P.J. Whitehouse et al.

    Nicotinic acetylcholine binding sites in Alzheimer's disease

    Brain Res.

    (1986)
  • M. Willard et al.

    Modulations of neurofilament axonal transport during the development of rabbit retinal ganglion cells

    Cell

    (1983)
  • S.A. Bayer

    Development of the hippocampal region in the rat. I. Neurogenesis examined with [3H]-thymidine autoradiography

    J. comp. Neurol.

    (1980)
  • Y. Ben-Ari et al.

    Giant synaptic potentials in immature rat CA3 hippocampal neurones

    J. Physiol. (Lond.)

    (1989)
  • I. Bergmann et al.

    Area-specific morphological and neurochemical maturation of non-pyramidal neurons in the rat hippocampus as revealed by parvalbumin immunocytochemistry

    Anat. Embryol.

    (1991)
  • C. Bichade et al.

    Glycine receptor a subunit and gephyrin expression in cultured spinal neurons: a quantitative analysis

    Eur. J. Neurosci.

    (1996)
  • L.I. Binder et al.

    Heterogeneity of microtubule-associated protein 2 during rat brain development

    Proc. natl Acad. Sci. U.S.A.

    (1984)
  • W. Bondareff et al.

    Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia

    Neurology

    (1982)
  • D.M. Bowen et al.

    Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies

    Brain

    (1976)
  • D.M. Bowen et al.

    Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease

    J. Neurochem.

    (1983)
  • H. Braak et al.

    Neuropathologic staging of Alzheimer-related changes

    Acta Neuropathol.

    (1991)

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