Role of galanin in synaptic transmission and plasticity in the CA1 area of the rodent hippocampus

Galanin is believed to be co-released with acetylcholine by neurones projecting from the medial septum and nucleus ofMeynert to the hippocampus in rodents. Galanin inhibits acetylcholine and glutamate release, thereby depressing excess neuronal excitability in the brain. Although this effect established galanin as an endogenous neuroprotective substance, released only during high frequency neuronal firing, it may also explain why it impairs memory and cognition in vivo. The sustained increase in glutamatergic synaptic strength following high frequency stimulation of hippocampal neurones, a phenomenon termed long-term potentiation (LTP), has been widely recognised as a model ofthe synaptic changes that may underlie learning and memory in vertebrates. It may thus be predicted that the physiological action ofgalanin at the cellular level would be to depress LTP, thereby causing an impairment in mnemonic processes mediated by the hippocampus. Experiments were designed to address aspects ofthis hypothesis, namely: (1) in vitro characterisation of the effect ofgalanin agonists and antagonists on synaptic transmission and plasticity in the CA1 area of rodent hippocampus and (2) investigation of glutamatergic synaptic plasticity in galanin knockout mice and their wild-type littermates. Exogenous galanin induced a dose-dependent increase in the slope of baseline fEPSPs, which appeared to be dependent on the pathways from CA3 to CA1 being intact, but it did not have any effect on paired-pulse facilitation ratios (PPF) in low concentration. However, in higher concentration, galanin induced a significant decrease in PPF in intact slices. In CA3-hemisected hippocampal slices the aforementioned effects did not occur. The effect of galanin on LTP and long-term depression (LTD) of glutamate mediated synaptic transmission in apical and basal dendrites of CA1 pyramidal neurones were investigated using both intracellular and extracellular recording techniques in vitro. LTP induced in either apical or basal dendrites of CA1 pyramidal neurones by different paradigms was significantly inhibited by galanin. Galanin also inhibited LTP in hippocampal slices prepared from wild-type mice. This effect was reversible by the known galanin antagonist, galantide (Ml5). Galanin did not affect isolated pure NMDA receptor-mediated postsynaptic potentials or the loss of spike frequency adaptation and increase in input resistance evoked by metabotropic glutamate receptor activation, indicating that its inhibition of LTP was downstream ofthese receptors. Galanin applied had no effect the expression of LTP indicating that galanin may inhibit LTP by interfering with kinase activity necessary for the induction of LTP, e.g. protein kinase C. Galanin did not affect the induction of LTD. Subsequent studies in the galanin-null transgenic mice yielded no effect on synaptic strength or paired pulse facilitation ratios. Galanin gene deletion caused a significant impairment of LTP, which was only observed in basal dendrites, the magnitude ofwhich increased with age. The underlying molecular mechanism for this impairment might be a significantly faster saturation of synaptic plasticity in the mutant mice in vivo, compared to wild-type mice. No effects of galanin were noted in mutant mice. This could suggest a developmental loss of galanin-responsive cells concomitant with global galanin gene deletion. In summary, galanin seems to have a modulatory effect on excitatory neurotransmitters in the hippocampus, such as glutamate, thereby delaying the neurodegenerative effect of age. The research described in this thesis is deemed of importance in biomedical research of drug therapy for protection against neurodegenerative disease

A Presynaptic Kainate Receptor Is Involved in Regulating the Dynamic Properties of Thalamocortical Synapses during Development

AbstractPrevious studies have shown that pharmacological activation of presynaptic kainate receptors at glutamatergic synapses facilitates or depresses transmission in a dose-dependent manner. However, the only synaptically activated kainate autoreceptor described to date is facilitatory. Here, we describe a kainate autoreceptor that depresses synaptic transmission. This autoreceptor is present at developing thalamocortical synapses in the barrel cortex, specifically regulates transmission at frequencies corresponding to those observed in vivo during whisker activation, and is developmentally down regulated during the first postnatal week. This receptor may, therefore, limit the transfer of high-frequency activity to the developing cortex, the loss of which mechanism may be important for the maturation of sensory processing

Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons

The neuropeptide galanin colocalizes with choline acetyltransferase, the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor induces a 3- to 4-fold increase in galanin gene expression in these neurons. Here we report the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits are associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day seven. This loss is associated with marked age-dependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These data provide unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons

Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons

The neuropeptide galanin colocalizes with choline acetyltransferase, the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor induces a 3- to 4-fold increase in galanin gene expression in these neurons. Here we report the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits are associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day seven. This loss is associated with marked age-dependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These data provide unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons