Summers

Neurobiology

text: Principles of Neural Science - Kandel, Schwartz and Jessell: acronyms end

XXII. Neuroactive Steroids 	  back to XXI. Amino Acid Tranmitters

	A. Peripheral steroids like F/B, P, T, E2 have receptors in
	   specific brain regions

		1. steroid concentrating neurons
		
		
		2. converting enzymes like P450aro (= aromatase, T ® E2) also


	B. Brain also makes steroids  (de novo and via metabolism)

		1. pregnenolone, DHEA, 5aDHP,
		  allopregnanolone=3a5aTHP, THDOC


			a. P450scc, 3b-HSD, 5a-reductase, 3a-oxidoreductase
                       present centrally in glia


	C. Peripheral steroids bind to classical
	    cytoplasmic/nuclear receptors to activate genomic actions


		1. especially immediate-early genes with products important
		    for neurochemical and endocrine function

			a. code for G-proteins, receptors,
			   protein kinases, transcription factors...


 	D. Non-genomic actions


  		1. de novo central neurosteroids bind to
		   ionotropic receptors, especially GABAA


			a. ligand-gated channels for ions (Cl-, Ca++)


		2. allosteric modulators of ion influx


			a. ionotropic receptors have multiple membrane
			    spanning subunits (usually 5) with more
				than one ligand binding site


				i. unique binding sites for steroids


		3. positive allosteric modulators of GABAA Cl- influx
		
		
			a. THP = allopregnanolone


			b. THDOC = tetrahydrodeoxycorticosterone


				i. less potent: androsterone (from DHEA)


			c. result: neuronal inhibition
			

				i. reversible structural regression in hippocampus


				ii. ratio between excitatory & inhibitory
				    steroids shape synaptic activity


			d. effects: anxiolytic, antiaggressive,
			   anesthetic, sedative, hypnotic


				i. blunted reaction to stimuli


					(1) antisocial behavior, inclination to substance abuse?


		4. negative allosteric modulators of GABAA Cl- influx


			a. PregS = pregnenolone sulfate


				i. less potent : Preg


			b. DHEAS = dehydroepiandrosterone sulfate


				i. less potent: DHEA, androstenedione,  


				ii. binding site distinct from PregS,
				    close to barbiturate binding site


			c. positively modulate NMDAGlu-R Ca++ influx


				i. excitatory steroids


			d. effects: enhance neuronal and glial survival &
			   structural growth, neuronal differentiation,
			   neuroprotective, enhance memory,  ­ anxiety,
			   ­ basal CNS arousal ­ convulsions, ­ seizures,
			   ­ sedation threshold


				i. positive correlations with longevity, vigor,
				   resistance to cancer and cardiovascular diseases


		5. specific G-protein mediated receptors have been
		    discovered for B, P & E2


	E. may alter neuro-microanatomy

		1. B reduces the number of dendritic spines
		    on hippocampal pyramidal cells
			
			
		2. E2 and 5aDHP increase dendritic
		   spines on hippocampal pyramidal cells

		3. affect behavior

			a. E2 increases and B decreases capacity for memory
			
				i. low [B] ® ñ memory
				   high [B] ® ¯  memory
		

XXIII. Neuromodulators and Neuropeptides

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