Synaptic transmission and plasticity in major excitatory hippocampal synapses of L1 conditional and CHL1 constitutive knockout mice (mus musculus L., 1758)

Lepsveridze, Eka (2006) Synaptic transmission and plasticity in major excitatory hippocampal synapses of L1 conditional and CHL1 constitutive knockout mice (mus musculus L., 1758). სადოქტორო thesis, Ilia State University.

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Abstract

The hippocampal formation is a group of structures within the limbic system, which includes the hippocampus, dentate gyrus, subiculum, presubiculum, parasubiculum and the entorhinal cortex. It plays an important role in processing of multimodal sensory information, novelty detection, emotions, learning and memory. Cell adhesion molecules are implicated in cell interactions during nervous system development and they are also recognized as important mediators of synaptic plasticity in the hippocampal formation. Among cell adhesion molecules, L1 has received a lot of attention since it was discovered as a transmembrane glycoprotein in the mouse. It subserves neuron-neuron adhesion via homophilic and heterophilic interactions with other adhesion and extracellular matrix molecules and mediates numerous neural functions. In humans, mutations in the L1 gene result in mental retardation, aphasia, shuffling gate, adducted thumbs, hydrocephalus as a result of stenosis of the aqueduct of Sylvius, spastic paraplegia and agenesis of the corpus callosum. Mouse mutants constitutively deficient in L1 (L1-/-) also show severe abnormalities in the development of the central and peripheral nervous systems. Conditional mutant (L1fy+) with ablation of L1 in the adult brain does not show any of the abnormalities in gross morphology described for the L1-/- mutant. Another interesting cell adhesion molecule is CHL1, which is a newly identified member of the L1 family. It is expressed in subpopulations of developing neurons in the central and peripheral nervous systems and persists at low levels in the mature brain in areas of high plasticity. The CALL gene, the human homologue of the mouse CHL1 gene, is linked to mental retardation and schizophrenia. The aim of our study was to identify excitatory synapses in the hippocampus and dentate gyrus, in which basal synaptic transmission and/or synaptic plasticity depend on expression of cell adhesion molecules L1 and CHL1, and to investigate the underlying mechanisms. To reach this aim, I have taken an advantage of availability of L1 conditional (L1fy+) and CHL1 constitutive knockout mice and performed extracellular recordings in acute hippocampal slices prepared from these animals and corresponding wild-type control mice to reveal genotypespecific changes in physiological parameters (amplitude of field excitatory postsynaptic potentials or currents, paired-pulse facilitation, post-tetanic or short-term potentiation, and LTP). Field potentials and synaptic currents have been recorded from synapses formed by (1) Schaffer collateral projections to the CA1 field; (2) lateral perforant path (LPP) and (3) medial perforant path (MPP) projections to the dentate gyrus; (4) direct perforant path projections to the CA3 and (5) CA1 fields; and (6) associational/commissural and (7) mossy fiber projections to the CA3 field. In addition, to investigate the influence of L1 molecule on L-type voltage-dependent Ca2+ channels, patch-clamp recordings of Ca2+ channel-transfected CHO cells have been used. Analysis of basal synaptic transmission and synaptic plasticity at above described major hippocampal excitatory synapses of L1 deficient mice and corresponding wild-type control animals revealed that LTP is specifically impaired in synapses formed by perforant path fibers on apical distal dendrites of CA1 and CA3 pyramidal neurons in L1fy+ mice. In light of impaired associative memory in the L1 mutant, our findings provide first evidence for importance of CA1 and CA3 perforant path projections for this kind of memory. Investigation of mechanisms underlying these abnormalities in LTP at the perforant path synapses in the CA3 region, by checking cholinergic modulation of perforant path and associational/commissural synapses in the CA3 field, uncovered that this system works normally in L1 conditional mutant animals. Examination of the role of NMDA receptors and L-type Ca2+ channels in induction and maintenance of LTP at perforant path projections to the CA3 field showed, that both are involved in this process and abnormal function of L-type Ca2+ channels may account for the difference in LTP between wild-type and knockout mice. Though pharmacological manipulations with L-type Ca2+ channels abolished differences between genotypes, the patch-clamp recording of CHO cells could not reveal direct influences of extracellular L1 on one subtype of neuronal VDCCs, suggesting that either other subtypes are affected or the influence of L1 on L-type Ca2+ channels is indirect. Analysis of CHL1 constitutive knockout mice revealed that deficiency in CHL1 molecule has a different impact on the synaptic plasticity at CA3-CA1 connections in animals of different ages, being normal in 2-month-old CHL1-deficient mice and reduced in 1-month-old and 9- month-old mutants. Investigation of mechanisms underlying impaired short- and long-term potentiation in 1 month-old mice revealed that increased activation of inhibitory interneurons might be responsible for this phenomenon. Apart from that, 2-month-old CHL1 deficient mice exhibit elevated levels of basal synaptic transmission in the dentate gyrus, which correlate with reduced behavioral response of these mutants to novel environmental stimuli. In summary, these results provide a new insight into synaptic functions of two cell adhesion molecules, demonstrating a synapse type- and Ca2+ channel-dependent impairment of synaptic plasticity in L1 deficient mice, and age- and GABAergic transmission-dependent deficit in synaptic plasticity in CHL1 deficient mutants.

Item Type: Thesis (სადოქტორო)
Subjects: Q Science > QP Physiology
Divisions: Institutes > Institute of Chemical Biology
Depositing User: Dr. Eka Lepsveridze
Date Deposited: 07 Apr 2015 09:09
Last Modified: 07 Apr 2015 09:09
URI: http://eprints.iliauni.edu.ge/id/eprint/231

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