Locally Synthetized 17-ß-Estradiol Reverses Amyloid-ß-42-Induced Hippocampal Long-Term Potentiation Deficits.

Amyloid beta 1-42 (Aß42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17ß-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17ß-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aß42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aß42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aß42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aß42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aß42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.

Adaptive perceptual responses to asymmetric rotation for testing otolithic function.

This study aimed to test the role of the otolithic system in self-motion perception by examining adaptive responses to asymmetric off-axis vertical rotation. Self-movement perception was examined after a conditioning procedure consisting of prolonged asymmetric sinusoidal yaw rotation of the head on a stationary body with hemicycle faster than the other hemicycle. This asymmetric velocity rotation results in a cumulative error in spatial self-motion perception in the upright position that persists over time. Head yaw rotation conditioning was performed in different head positions: in the upright position to activate semicircular canals and in the supine and prone positions to activate both semicircular canals and otoliths with the phase of otolithic stimulation reversed with respect to activation of the semicircular canals. The asymmetric conditioning influenced the cumulative error induced by four asymmetric cycles of whole-body vertical axis yaw rotation. The magnitude of this error depended on the orientation of the head during the conditioning. The error increased by 50% after upright position conditioning, by 100% in the supine position, and decreased by 30% in the prone position. The enhancement and reduction of the perceptual error are attributed to otolithic modulation because of gravity influence of the otoliths during the conditioning procedure in supine and prone positions. These findings indicate that asymmetric velocity otolithic activation induces adaptive perceptual errors such as those induced by semicircular canals alone, and this adaptation may be useful in testing dynamic otolithic perceptual responses under different conditions of vestibular dysfunction.

Auditory perception is influenced by the orientation of the trunk relative to a sound source.

The study investigated how hearing depends on the whole body, head and trunk orientation relative to a sound source. In normal hearing humans we examined auditory thresholds and their ability to recognize logatomes (bi-syllabic non-sense words) at different whole body, head and trunk rotation relative to a sound source. We found that auditory threshold was increased and logatome recognition was impaired when the body or the trunk were rotated 40° away from a sound source compared to when the body or the trunk was oriented towards the sound source. Conversely, no effects were seen when only the head was rotated. Further, an increase of thresholds and impairment of logatome recognition were also observed after unilateral vibration of dorsal neck muscles that induces, per se, long-lasting illusory trunk displacement relative to the head. Thus, our findings support the idea that processing of acoustic signals depends on where a sound is located within a reference system defined by the subject's trunk coordinates.

Different time course of compensation of subjective visual vertical and ocular torsion after acute unilateral vestibular lesion.

PURPOSE: Time course of the recovery of otolithic dis-function caused by superior vestibular neuritis has been examined in fifteen patients. METHODS: The subjective visual vertical (SVV) and the ocular cyclotorsion (OT) have been measured four times after the acute episode up to 1 year RESULTS: In most of the patients the SVV tilt returned to control values within few months (3-6 months) after the acute episode, while OT remained out of normal range in almost all patients a year later. CONCLUSION: The abnormal OT observed after 1 year from the acute episode of vestibular neuritis, suggests that the otolithic receptors remained altered for several months and the OT may be a good indicator of the entity of the residual peripheral otolithic lesion. Moreover, the dissociation between the SVV tilt recovery and that of OT supports the issue that the two signs of the otolithic disfunction are only partially linked each other with centrally or peripherally distinct re-balancing circuits.

Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat.

Electrophysiological recordings were used to investigate the role of the local synthesis of 17ß-estradiol (E2) and 5α-dihydrotestosterone (DHT) on synaptic long-term effects induced in the hippocampal CA1 region of male rat slices. Long-term depression (LTD) and long-term potentiation (LTP), induced by different stimulation patterns, were examined under the block of the DHT synthesis by finasteride (FIN), and the E2 synthesis by letrozole (LET). We used low frequency stimulation (LFS) for LTD, high frequency stimulation (HFS) for LTP, and intermediate patterns differing in duration or frequency. We found that FIN reverted the LFS-LTD into LTP and enhanced LTP induced by intermediate and HFSs. These effects were abolished by exogenous DHT at concentration higher than the basal one, suggesting a stimulus dependent increase in DHT availability. No effect on the synaptic responses was observed giving DHT alone. Moreover, we found that the inhibition of E2 synthesis influenced the HFS-LTP by reducing its amplitude, and the exogenous E2 either enhanced HFS-LTP or reverted the LFS-LTD into LTP. The equivalence of the E2 concentration for rescuing the full HFS-LTP under LET and reverting the LFS-LTD into LTP suggests an enhancement of the endogenous E2 availability that is specifically driven by the HFS. No effect of FIN or LET was observed on the responses to stimuli that did not induce either LTD or LTP. This study provides evidence that the E2 and DHT availability combined with specific stimulation patterns is determinant for the sign and amplitude of the long-term effects.

Selective contribution of each hamstring muscle to anterior cruciate ligament protection and tibiofemoral joint stability in leg-extension exercise: a simulation study.

A biomechanical model was developed to simulate the selective effect of the co-contraction force provided by each hamstring muscle on the shear and compressive tibiofemoral joint reaction forces, during open kinetic-chain knee-extension exercises. This model accounts for instantaneous values of knee flexion angle [Formula: see text], angular velocity and acceleration, and for changes in magnitude, orientation, and application point of external resistance. The tibiofemoral shear force (TFSF) largely determines the tensile force on anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL). Biceps femoris is the most effective hamstring muscle in decreasing the ACL-loading TFSF developed by quadriceps contractions for [Formula: see text]. In this range, the semimembranosus generates the dominant tibiofemoral compressive force, which enhances joint stability, opposes anterior/posterior tibial translations, and protects cruciate ligaments. The semitendinosus force provides the greatest decreasing gradient of ACL-loading TFSF for [Formula: see text], and the greatest increasing gradient of tibiofemoral compressive force for [Formula: see text]. However, semitendinosus efficacy is strongly limited by its small physiological section. Hamstring muscles behave as a unique muscle in enhancing the PCL-loading TFSF produced by quadriceps contractions for [Formula: see text]. The levels of hamstrings co-activation that suppress the ACL-loading TFSF considerably shift when the knee angular acceleration is changed while maintaining the same level of knee extensor torque by a concurrent adjustment in the magnitude of external resistance. The knowledge of the specific role and the optimal activation level of each hamstring muscle in ACL protection and tibiofemoral stability are fundamental for planning safe and effective rehabilitative knee-extension exercises.

Effectiveness of Focal Muscle Vibration in the Recovery of Neuromotor Hypofunction: A Systematic Review.

Adequate physical recovery after trauma, injury, disease, a long period of hypomobility, or simply ageing is a difficult goal because rehabilitation protocols are long-lasting and often cannot ensure complete motor recovery. Therefore, the optimisation of rehabilitation procedures is an important target to be achieved. The possibility of restoring motor functions by acting on proprioceptive signals by unspecific repetitive muscle vibration, focally applied on single muscles (RFV), instead of only training muscle function, is a new perspective, as suggested by the effects on the motor performance evidenced by healthy persons. The focal muscle vibration consists of micro-stretching-shortening sequences applied to individual muscles. By repeating such stimulation, an immediate and persistent increase in motility can be attained. This review aims to show whether this proprioceptive stimulation is useful for optimising the rehabilitative process in the presence of poor motor function. Papers reporting RFV effects have evidenced that the motor deficits can be counteracted by focal vibration leading to an early and quick complete recovery. The RFV efficacy has been observed in various clinical conditions. The motor improvements were immediate and obtained without loading the joints. The review suggests that these protocols can be considered a powerful new advantage to enhance traditional rehabilitation and achieve a more complete motor recovery.

Induction and Cancellation of Self-Motion Misperception by Asymmetric Rotation in the Light.

Asymmetrical sinusoidal whole-body rotation sequences with half-cycles at different velocities induce self-motion misperception. This is due to an adaptive process of the vestibular system that progressively reduces the perception of slow motion and increases that of fast motion. It was found that perceptual responses were conditioned by four previous cycles of asymmetric rotation in the dark, as the perception of self-motion during slow and fast rotations remained altered for several minutes. Surprisingly, this conditioned misperception remained even when asymmetric stimulation was performed in the light, a state in which vision completely cancels out the perceptual error. This suggests that vision is unable to cancel the misadaptation in the vestibular system but corrects it downstream in the central perceptual processing. Interestingly, the internal vestibular perceptual misperception can be cancelled by a sequence of asymmetric rotations with fast/slow half-cycles in a direction opposite to that of the conditioning asymmetric rotations.

Skull-vibration-induced nystagmus test in patients who are candidates for intratympanic gentamicin injection.

Objective: This study aims to evaluate the utility of the skull-vibration-induced nystagmus test (SVINT) in the selection of patients with Ménière's disease (MD) for intratympanic injection of gentamicin. To date the indications for this treatment have been based only on subjective elements. Methods: A retrospective study was performed in 20 patients diagnosed with unilateral MD. SVINT were performed monthly and the evoked responses were evaluated. After 6 months, the results from patients who were candidates for gentamicin treatment (G group) were compared with those who did not need it (nG group). Correlation with Dizziness Handicap Inventory (DHI) score was evaluated. Results: 120 tests were performed. Positive SVINTs were identified in 52 cases (43.3%) and included excitatory nystagmus in 18 (34.7%), inhibitory nystagmus in 28 (53.8%), and atypical pattern in 6 cases (11.5%). A significant increase excitatory nystagmus was recorded in group G (p = 0.00001). Moreover, there was a significant increase in the DHI score in group G compared with the nG group (p < 0.0001) and in patients with evoked excitatory nystagmus. Conclusions: The finding of excitatory nystagmus during SVINTs performed on several occasions in the follow-up prior to intratympanic injection of gentamicin strengthens this therapeutic choice.

Evaluation of Cochlear Symptoms in Migraine Patients without Vestibular Migraine and/or Ménière's Disease.

Migraine pathogenic pathways may selectively target the cochlea. A qualitative and quantitative analysis of cochlear symptoms in migraine patients without vestibular migraine and/or Méniere's disease was conducted. We examined 60 consecutive patients with history of cochlear symptoms, including fullness, tinnitus, and hearing loss. Patients were divided into two groups based on migraine history: M (migraine) and nM (no migraine). The incidence of migraine was compared to a homogeneous control group with dysfunctional and inflammatory dysphonia without cochlear symptoms. The type, time of onset, recurrence, bilaterality of symptoms, and hearing threshold were analyzed. The incidence of migraine was significantly higher (p = 0.04) in patients with cochlear symptoms than in the control group. The onset of symptoms is significantly earlier (p < 0.05) in the presence of migraine. The fullness, recurrence, and bilaterality of symptoms are associated with migraine in a statistically significant way (p < 0.05). Pure tone audiometry shows a statistically significant increase in the hearing threshold (500-1000 Hz) in group M. Based on developing findings, cochlear migraine may be considered as a novel clinical entity, like vestibular migraine. It would be the expression, in the absence of vertiginous symptoms, of a selective suffering of the anterior labyrinth by known operating mechanisms of migraine.

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature.

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K(+) channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1(V408A/+)). Here, we investigated the neuromuscular transmission of Kv1.1(V408A/+) ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve-muscle from Kv1.1(+/+) and Kv1.1(V408A/+) mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca(2+) signals that occurred abnormally only in preparations dissected from Kv1.1(V408A/+) mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca(2+) homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K(+) channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult.

Disruption of self-motion perception without vestibular reflex alteration in ménière's disease.

BACKGROUND: Self-motion misperception has been observed in vestibular patients during asymmetric body oscillations. This misperception is correlated with the patient's vestibular discomfort. OBJECTIVE: To investigate whether or not self-motion misperception persists in post-ictal patients with Ménière's disease (MD). METHODS: Twenty-eight MD patients were investigated while in the post-ictal interval. Self-motion perception was studied by examining the displacement of a memorized visual target after sequences of opposite directed fast-slow asymmetric whole body rotations in the dark. The difference in target representation was analyzed and correlated with the Dizziness Handicap Inventory (DHI) score. The vestibulo-ocular reflex (VOR) and clinical tests for ocular reflex were also evaluated. RESULTS: All MD patients showed a noticeable difference in target representation after asymmetric rotation depending on the direction of the fast/slow rotations. This side difference suggests disruption of motion perception. The DHI score was correlated with the amount of motion misperception. In contrast, VOR and clinical trials were altered in only half of these patients. CONCLUSIONS: Asymmetric rotation reveals disruption of self-motion perception in MD patients during the post-ictal interval, even in the absence of ocular reflex impairment. Motion misperception may cause persistent vestibular discomfort in these patients.

Adaptive Balance in Posterior Cerebellum.

Vestibular and optokinetic space is represented in three-dimensions in vermal lobules IX-X (uvula, nodulus) and hemisphere lobule X (flocculus) of the cerebellum. Vermal lobules IX-X encodes gravity and head movement using the utricular otolith and the two vertical semicircular canals. Hemispheric lobule X encodes self-motion using optokinetic feedback about the three axes of the semicircular canals. Vestibular and visual adaptation of this circuitry is needed to maintain balance during perturbations of self-induced motion. Vestibular and optokinetic (self-motion detection) stimulation is encoded by cerebellar climbing and mossy fibers. These two afferent pathways excite the discharge of Purkinje cells directly. Climbing fibers preferentially decrease the discharge of Purkinje cells by exciting stellate cell inhibitory interneurons. We describe instances adaptive balance at a behavioral level in which prolonged vestibular or optokinetic stimulation evokes reflexive eye movements that persist when the stimulation that initially evoked them stops. Adaptation to prolonged optokinetic stimulation also can be detected at cellular and subcellular levels. The transcription and expression of a neuropeptide, corticotropin releasing factor (CRF), is influenced by optokinetically-evoked olivary discharge and may contribute to optokinetic adaptation. The transcription and expression of microRNAs in floccular Purkinje cells evoked by long-term optokinetic stimulation may provide one of the subcellular mechanisms by which the membrane insertion of the GABAA receptors is regulated. The neurosteroids, estradiol (E2) and dihydrotestosterone (DHT), influence adaptation of vestibular nuclear neurons to electrically-induced potentiation and depression. In each section of this review, we discuss how adaptive changes in the vestibular and optokinetic subsystems of lobule X, inferior olivary nuclei and vestibular nuclei may contribute to the control of balance.

Rapid Estrogenic and Androgenic Neurosteroids Effects in the Induction of Long-Term Synaptic Changes: Implication for Early Memory Formation.

Mounting experimental evidence demonstrate that sex neuroactive steroids (neurosteroids) are essential for memory formation. Neurosteroids have a profound impact on the function and structure of neural circuits and their local synthesis is necessary for the induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and for neural spine formation in different areas of the central nervous system (CNS). Several studies demonstrated that in the hippocampus, 17ß-estradiol (E2) is necessary for inducing LTP, while 5α-dihydrotestosterone (DHT) is necessary for inducing LTD. This contribution has been proven by administering sex neurosteroids in rodent models and by using blocking agents of their synthesis or of their specific receptors. The general opposite role of sex neurosteroids in synaptic plasticity appears to be dependent on their different local availability in response to low or high frequency of synaptic stimulation, allowing the induction of bidirectional synaptic plasticity. The relevant contribution of these neurosteroids to synaptic plasticity has also been described in other brain regions involved in memory processes such as motor learning, as in the case of the vestibular nuclei, the cerebellum, and the basal ganglia, or as the emotional circuit of the amygdala. The rapid effects of sex neurosteroids on neural synaptic plasticity need the maintenance of a tonic or phasic local steroid synthesis determined by neural activity but might also be influenced by circulating hormones, age, and gender. To disclose the exact mechanisms how sex neurosteroids participate in finely tuning long-term synaptic changes and spine remodeling, further investigation is required.

Bidirectional Synaptic Plasticity Is Driven by Sex Neurosteroids Targeting Estrogen and Androgen Receptors in Hippocampal CA1 Pyramidal Neurons.

Neuroactive estrogenic and androgenic steroids influence synaptic transmission, finely modulating synaptic plasticity in several brain regions including the hippocampus. While estrogens facilitate long-term potentiation (LTP), androgens are involved in the induction of long-term depression (LTD) and depotentiation (DP) of synaptic transmission. To examine sex neurosteroid-dependent LTP and LTD in single cells, patch-clamp recordings from hippocampal CA1 pyramidal neurons of male rats and selective antagonists for estrogen receptors (ERs) and androgen (AR) receptors were used. LTP induced by high-frequency stimulation (HFS) depended on activation of ERs since it was prevented by the ER antagonist ICI 182,780 in most of the neurons. Application of the selective antagonists for ERα (MPP) or ERß (PHTPP) caused a reduction of the LTP amplitude, while these antagonists in combination, prevented LTP completely. LTP was never affected by blocking AR with the specific antagonist flutamide. Conversely, LTD and DP, elicited by low-frequency stimulation (LFS), were impeded by flutamide, but not by ICI 182,780, in most neurons. In few cells, LTD was even reverted to LTP by flutamide. Moreover, the combined application of both ER and AR antagonists completely prevented both LTP and LTD/DP in the same neuron. The current study demonstrates that the activation of ERs is necessary for inducing LTP in hippocampal pyramidal neurons, whereas the activation of ARs is required for LTD and DP. Moreover, both estrogen- and androgen-dependent LTP and LTD can be expressed in the same pyramidal neurons, suggesting that the activation of sex neurosteroids signaling pathways is responsible for bidirectional synaptic plasticity.

ERG voltage-gated K+ channels regulate excitability and discharge dynamics of the medial vestibular nucleus neurones.

The discharge properties of the medial vestibular nucleus neurones (MVNn) critically depend on the activity of several ion channel types. In this study we show, immunohistochemically, that the voltage-gated K(+) channels ERG1A, ERG1B, ERG2 and ERG3 are highly expressed within the vestibular nuclei of P10 and P60 mice. The role played by these channels in the spike-generating mechanisms of the MVNn and in temporal information processing was investigated electrophysiologically from mouse brain slices, in vitro, by analysing the spontaneous discharge and the response to square-, ramp- and sinusoid-like intracellular DC current injections in extracellular and whole-cell patch-clamp studies. We show that more than half of the recorded MVNn were responsive to ERG channel block (WAY-123,398, E4031), displaying an increase in spontaneous activity and discharge irregularity. The response to step and ramp current injection was also modified by ERG block showing a reduction of first spike latency, enhancement of discharge rate and reduction of the slow spike-frequency adaptation process. ERG channels influence the interspike slope without affecting the spike shape. Moreover, in response to sinusoid-like current, ERG channel block caused frequency-dependent gain enhancement and phase-lead shift. Taken together, the data demonstrate that ERG channels control the excitability of MVNn, their discharge regularity and probably their resonance properties.

Role of group II metabotropic glutamate receptors 2/3 and group I metabotropic glutamate receptor 5 in developing rat medial vestibular nuclei.

In brainstem slices from developing rats, metabotropic glutamate receptors mGluR2/3 and mGluR5 play different inhibitory roles in synaptic transmission and plasticity of the medial vestibular nuclei. The mGluR2/3 block (LY341495) reduces the occurrence of long-term depression after vestibular afferent high frequency stimulation at P8-P10, and increases that of long-term potentiation, while the mGluR5 block prevents high frequency stimulation long-term depression. Later on, the receptor block does not influence high frequency stimulation effects. In addition, while mGluR2/3 agonist (APDC) always provokes a transient reduction of synaptic responses, that of mGluR5 (CHPG) induces long-term depression per se at P8-P10. These results show a key role of mGluR5 in inducing high frequency stimulation long-term depression in developing medial vestibular nuclei, while mGluR2/3 modulate synaptic transmission, probably through presynaptic control of glutamate release.

Long-lasting effects of neck muscle vibration and contraction on self-motion perception of vestibular origin.

OBJECTIVE: To show that neck proprioceptive input can induce long-term effects on vestibular-dependent self-motion perception. METHODS: Motion perception was assessed by measuring the subject's error in tracking in the dark the remembered position of a fixed target during whole-body yaw asymmetric rotation of a supporting platform, consisting in a fast rightward half-cycle and a slow leftward half-cycle returning the subject to the initial position. Neck muscles were relaxed or voluntarily contracted, and/or vibrated. Whole-body rotation was administered during or at various intervals after the vibration train. The tracking position error (TPE) at the end of the platform rotation was measured during and after the muscle conditioning maneuvers. RESULTS: Neck input produced immediate and sustained changes in the vestibular perceptual response to whole-body rotation. Vibration of the left sterno-cleido-mastoideus (SCM) or right splenius capitis (SC) or isometric neck muscle effort to rotate the head to the right enhanced the TPE by decreasing the perception of the slow rotation. The reverse effect was observed by activating the contralateral muscle. The effects persisted after the end of SCM conditioning, and slowly vanished within several hours, as tested by late asymmetric rotations. The aftereffect increased in amplitude and persistence by extending the duration of the vibration train (from 1 to 10min), augmenting the vibration frequency (from 5 to 100Hz) or contracting the vibrated muscle. Symmetric yaw rotation elicited a negligible TPE, upon which neck muscle vibrations were ineffective. CONCLUSIONS: Neck proprioceptive input induces enduring changes in vestibular-dependent self-motion perception, conditional on the vestibular stimulus feature, and on the side and the characteristics of vibration and status of vibrated muscles. This shows that our perception of whole-body yaw-rotation is not only dependent on accurate vestibular information, but is modulated by proprioceptive information related to previously experienced position of head with respect to trunk. SIGNIFICANCE: Tonic proprioceptive inflow, as might occur as a consequence of enduring or permanent head postures, can induce adaptive plastic changes in vestibular-dependent motion sensitiveness. These changes might be counteracted by vibration of selected neck muscles.

Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long-term potentiation or depression is induced in hippocampus of male rat.

Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17ß-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.

Endogenous 17ß-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.

17ß-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease.